Table of contents :
that, upon binding to MHC I,
become phosphorylated by c-Src
and allow recruitment of SHP1
/
PTPN6 and/or SHP2,
LCK
and talin :
. CD94/NKG2A is continuously
recycled between the cell surface and cytoplasm,
and that this recycling is independent of ligation
and the transmission of inhibitory signals.
Because CD94/NKG2A receptors are in the constant
presence of ligand expressed by normal cells, the
detachment of recycling from ligation/inhibitory
processes likely facilitates the maintenance of a
pool of CD94/NKG2A receptors on the cell surface
available for interaction with HLA-E
envelope-containing) => ZAP70
and Syk
=> PI(3)K STP,
inhibits NK cell cytotoxicity by a direct and
specific interaction with the activating
receptor NKp30, leading to dissociation of the
linked CD3z from
NKp30ref]
, ?-containing) => ZAP70
and Syk
=> PI(3)K STP.
This STP is required to trigger NKG2D-dependent
cytokine release by NK cells., ? and AKT
STP !) pathway regulates innate
immune system ligands of the NKG2D receptorref
STP
that control intrinsic apoptosis and presumably
reflects the fact that "fuzzy" decision-making
mechanisms are more resistant to errors than discrete,
all-or-none processes. Peroxiredoxin
(PRDX1) is required in both NK cells and
non-immune cells for optimal NK function. .
and CD127 (IL-7R) are molecular
markers of a pathway of mouse NK cell development that
originates in the thymus. Thymus-derived CD127+
NK cells repopulated peripheral lymphoid organs, and
their homeostasis was strictly dependent on GATA-3 and
IL-7. The CD127+ NK cells had a distinct
phenotype (CD11bloCD16-CD69hiLy49lo)
and unusual functional attributes, including reduced
cytotoxicity but considerable cytokine production. Those
characteristics are reminiscent of human CD56hiCD16-
NK cells, which we found expressed CD127 and had more
GATA-3 expression than human CD56+CD16+
NK cells. Bone marrow and thymic NK cell pathways generate
distinct mouse NK cells with properties similar to those
of the two human CD56 NK cell subsetsref.
or ...
+ ? to become a :
,
G-CSF-R
and IL-7Ra : whereas the
transcription factor PU.1 regulates IL-7R expression
in mouse pro–B cells via a GGAA motif, GA binding
protein (GABP) ab2
binds to this site and is essential in the regulation
of IL-7R expression in T cells, where PU.1 is not
expressedref) is crucial for
migration of early thymic immigrants from the
corticomedullary region to the subcapsular region (more
important in the adult structured thymus) and migration of
positively selected thymocytes from the cortex to the
medulla (more important in newborns than in adult mice)ref1,
ref2.
The only progenitors in blood with efficient T lineage
potential are Lin-SCA1hic-kithi
(LSK cells). The blood LSK population, like its
counterpart in the bone marrow, contains HSCs and
nonrenewing, multipotent progenitors, including early
lymphoid progenitors and CD62L+ cells
previously described as efficient T lineage progenitors.
CLPs can not be identified in the circulation, suggesting
they are not physiological T lineage precursors. Blood LSK
cells are the principal circulating progenitors with T
lineage potentialref.
-dependent responses. ETPs
can also develop via a common lymphoid progenitors
(CLP)-independent pathway. .
,
IL-2, IL-6, IL-7, + Notch1
on T cells (vs. mNumb)
--- Notch ligands (on TECs), ... +CCR7+)
: it is located in the deep cortex and needs CD117 / c-kit
/ SCFR/
CD132
/ gc, preTcRa/ CD132
/ gc, BCL11B,
and IL-7Ra
to maturate.+,
cCD3deg).
It
is located in the midcortex.,
BMP4,
myeloid-cell
leukemia
1 (MCL1)ref
(a component of the signalling pathway downstream of IL-7, which binds BIM
and prevents BIM-mediated activation of the pro-apoptotic
proteins BAK1
and BAX)
+)
: it is located in the outer third of the cortex and
needs ..., ZAP70,
Syk, Fyn, CD117 / c-kit
/ SCFR,
IL-2Rg,
IL-7Ra,
TCF1a, GATA3ref,
Rho, LAT,
SLP76,
Vav1,
c-Mybref,
survivinref1,
ref2,
and Runx2
protein levels, only
required for preTCR induced proliferation but dispensable
for developmental progression from the DN to the DP stageref.
,
but attenuate GATA3
expression, recruit DNA methyltransferases (Dnmts) to
the Il4-Il13 locus and downregulate IL-4
expression as they mature into T cells. They contain
mature TCRB (V to DJ) rearrangementsref, IL-15 (which
induces local chromatin modifications specific for the
variable gd-region gene
segment and enhanced accessibility conducive to
subsequent targeted gene rearrangement. This
cytokine-directed tissue-specific TCR repertoire
formation probably reflects distinct TCR repertoire
selection criteria for gd
and ab T cell lineages
adopted for different antigen-recognition strategiesref)
RA-RO+NKG2D+, z+h+TcRgdhi), but not by adult long-term
reconstituting
HSC (LT-HSC)., but not by adult long-term
reconstituting
HSC (LT-HSC).RBhi103
/ aE
integrin+134
/ OX40lo178
/ Apo1L / FasLloLy-6Clo
: they express high levels of FasL gene whose
surface expression is controlled at
posttranscriptional level. Their
TcR binds to), a virus that is
known to cause the upregulation of MIC
expression by infected cells. Clones derived
from transplanted patients, including Vd1+,
Vd3+
and Vd5+
cells, responded strongly to CMV-infected cellsref
[13], killed the infected targets and limited
CMV propagation in vitro. This reactivity
was specific for CMV among herpesviridae but the
same clones also responded to intestinal
epithelial tumor cells, again suggesting the
involvement of an (unidentified) autologous
ligand.ref
: 4 different phosphoantigens termed TUBag1 to
TUBag4 with a common
3-formyl-1-butyl-pyrophosphate moiety and
isopentenyl-pyrophosphate have been isolated
and identified from mycobacteria. IPP does not
induce down-modulation of the TcR·CD3 complex,
which likely results in the highly sustained
signaling and release of high levels of TNF-aref.
The mechanisms by which mycobacteria induce gdT cell reactivity are
not fully defined. Previous studies have shown
cell contact dependency, suggesting a
requirement for antigen presentation, and a
current study using a human Vg9Vd2+
clone capable of responding to alkylphosphate,
alkylamine and aminobisphosphonate, as well as
purified protein derivative (PPD) from Mycobacterium
tuberculosis, shows that only human
cells satisfy the contact requirement, for all
of these antigensref
[11].,
recently reported to induce bovine gd T cells to IFN-g production in the
presence of IL-2 and accessory cellsref
[10]. : phosphoantigens
exert bioactivities on gd
T cells with similar potencies to the
mycobacterial phosphoantigens at 5-15 nM
concentrationref : in samples
obtained 4 to 6 days after the onset of the
disease, the mean percentage (± the standard
deviation) of Vg9Vd2+ T cells
among CD3+ cells was 1.0% ± 0.5%,
compared to 5.0% ± 3.9% in healthy control
subjects (P < 0.001). Thereafter, a
pronounced increase occurred and at 2 to 7
weeks after onset, mean peak levels were as
high as 15%. During the next 6 months, values
slowly declined, although without reaching the
normal range. Percentages of gd+ T cells
expressing TNF-a or
IFN-g in response
to phorbol myristate acetate were assayed in
vitro. At 14 to 16 days after the onset
of disease, the expression of both cytokines
was increased (P < 0.01), whereas at 5 to 7
weeks, the expression of tumor necrosis factor
alpha was decreased (P < 0.05), possibly
reflecting modulation of an inflammatory
response. In conclusion, Pontiac fever was
found to be associated with a pronounced and
long-lasting expansion of Vg9Vd2 T cells, implying
that the subset may also be
pathophysiologically important in a mild and
transient form of intracellular bacterial
diseases. Surprisingly, the expansion was
preceded by a depletion of circulatory Vg9Vd2
T cells. Possibly, Vg9Vd2 T cells are
initially recruited to a site of infection
before they expand in response to antigen and
occur in high numbers in blood.ref (but not after
tularemia vaccination)ref1,
ref2 (zoledronate and
pamidronate) (during tuberculoid
leprosy), which block the
mevalonate pathway in target cells, leading to
accumulation of natural phosphoantigens that
in turn activate Vg9Vd2+ cells.
Activation of primary gd T cells
by pamidronate strictly depends on the
presence of monocyte-lineage cells, unlike
that by pyrophosphomonoesters. Thus, although
pamidronate induced cell clustering,
proliferation, and IFN-g
production of gd T cells
in the culture of PBMC, it failed to induce
any of these activities in the culture of
purified primary gd T cells.
By adding back the purified monocytes,
however, both cell clustering and IFN-g production of T
cells by pamidronate could be restored. The
pamidronate-pulsed, but not untreated,
myelomonocytic line, THP-1, was capable of
activating the purified gd T cells
to produce IFN-g,
which was associated with the down-regulation
of gd
TCR. Furthermore, pamidronate-pulsed THP-1
cells were significantly more susceptible to gd
T cell-mediated cytotoxicity than untreated
THP-1. Also, TCR-defective Jurkat T cells
transfected with gd TCR genes
produced a significant level of IL-2 in
response to the pamidronate-pulsed THP-1
cells. These results have suggested strongly
that human T cells are functionally
activated via TCR by aminobisphosphonate
Ag presented on the surface of monocyte
lineage cells rather than directly by its free
formref) cellsref : in rodents, intravaginal
gd T cells provide
innate protection against intravaginal
infection and promote CD4+ Th1-dependent
systemic immunity to the virus (5)ref.
Phosphoantigen-reactive Vg9Vd2+ cells
were also found to infiltrate lesions of
patients with genital herpesref
[12], consistent with the possibility of an
inducible autologous ligand for this subset of
gd T cells., capable of causing
urethritis and respiratory disease and
associated with the deterioration of the
immune system in AIDS patients, was shown to
elicit a response in human Vg9Vd2+
T cellsref
[6]. The difference is explained by the
ability of this Mycoplasma species to
synthesize isoprenoid precursors which are
stimulatory for ?? T cells; most of the others
have lost this ability during evolution.refref
(elevated during the acute infection and
remain elevated for at least 4 weeks during
convalescence) : in vitro
exposure of naive human PBMC results
in cell proliferation and the production of
IFN-g, IL-12, and
TNF-a. Cell
proliferation was highest when using high
numbers of Leptospira. Optimal cell
proliferation occurred at 6–8 days, and the
majority of cells contained in these cultures
were gd T cells.
These cultures showed a 10- to 50-fold
expansion of gd T
cells compared with the initial cellular
input. Additionally, these cultures contained
elevated numbers of NK cells. In contrast,
exposure of PBMC to low numbers of Leptospira
failed to induce gd
T cell or NK cell expansion, but induced
significant ab T
cell expansion. V9/V2 were expressed on all /
T cells expanded by exposure of PBMC to Leptospira.
Leptospira stimulation of purified TCR+
T cells, obtained from 8-day cultures of Leptospira-stimulated
PBMC, induced high levels of IFN-g production, but no
cell proliferation, suggesting that such
stimulation of T cells did not depend on
specialized accessory cells or Ag processing.
Finally, in patients with acute leptospirosis,
there was a significant (4- to 5-fold)
increase in the number of peripheral blood TCR+
T cells. These results indicate that Leptospira
can activate gd T
cells and ab T
cells and will guide further investigations
into the roles of these T cell populations in
host defense and/or the pathology of
leptospirosisref : Vg9Vd2 cells is drastically
increased in the peripheral blood of patients
during the acute phase of infection. Vg9Vd2
T cells use contact-dependent mechanisms, such
as the release of lytic granules and
Fas-mediated signals, to decrease
intracellular B. suis through lysis of
infected macrophages, but these mechanisms
have little impact on Brucella
survival. Moreover, soluble factors (including
LL-37ref)
secreted by Vg9Vd2 T cells can directly
affect B. suis survival through their
potent bactericidal effectsref1,
ref2-type cytokines : TNF-a, IFN-g and MIF (the latter indirectly increases
TNF-a and IL-1b secretion,
counteracting the inhibitory effect of
glucocorticoids). They represent 100% lymphocytes in
fetal liver and 5% total adult peripheral blood
lymphocytes. They are considered to be innate lymphocytes,
although in the perinatal period sequences express
N-diversification and cells have a naive
phenotype (CD45 / B220 /
LCARA+). They express NKG2D for reception
of costimulatory signals from MICA and MICB, which
are not sufficient to activate these cells.
Some recognize CD1C.
ref.
In humans, the expansion of T cell subsets has
been documented in Mycobacterium
spp. infectionref
and in immunocompromised transplanted patients
infected with the HHV-5
/
CMVref1,
ref2,
ref3.
> Th2 cytokine
release profile) or killer
cells (even on activated macrophages). They have
pro-inflammatory functions early in disease, but
anti-inflammatory during the late stage of disease. , which
mediates recruitment responses to the LN-resident
chemokines CCL19 and CCL21, but instead express a
range of receptors for inflammatory chemokinesref
[10]. Furthermore, the expression of chemokine
receptors for homing to healthy peripheral tissues,
such as those described in ab
T cellsref1,
ref2,
ref3,
ref4
2, 5, 8 and 9, have not been found in peripheral blood
Vg9Vd2+
T cells. mRNA,
implying that these receptors are important for cell
differentiation or function. However, multiple efforts
to detect TLR2 protein on the cell surface or in
cytoplasmic compartments gave inconsistent results.
Functional assays confirmed that human Vg9Vd2
T cells could respond to the TLR2 agonist Pam3Cys, but
the response required coincident stimulation through
the gd TcRref.
A tense functional relationship with myeloid cells : mostly through studies of inflammation, it has become clear that gd T cells engage in regulatory interactions with macrophages, granulocytes and DCs. However, even in healthy normal tissues, interactions with myeloid cells are frequent. A histological study of the mouse lung showed that at any given time, about half of the resident gd T cells are in direct contact with MHC II+ cells, most of which appear to be DCsref [32•]. Contacts with F4/80+ cells are also frequent, and a comparison between gd and ab T cells and their respective contacts revealed a bias of the gd T cells for myeloid contacts. These interactions suggest a monitoring of myeloid cells by the gd T cells.
Figure 2. Frequent contacts between gd T cells and leukocytes of the innate system in the lung. A histological snapshot of the normal lung (untreated C57BL/6 mice) shows most pulmonary gd T cells in direct contact with other leukocytes, including (a) MHC class II+, (b) F4/80+ and (c) DEC-205+ cells, in descending order of frequency. Preferential contacts with myeloid cells distinguishes gd T cells from ab T cells in the lung. Frozen lung tissue was stained with monoclonal antibodies specific for the indicated leukocyte markers and TCR-d. gd T cells appear in red, other leukocytes in blue and tissue autofluorescence in green (false colors). Reproduced in modified form with permission from Wands et al.ref [32•].
Following Listeria monocytogenes infection, gd T cells regulate the inflammatory response. In their absence, inflammatory infiltrates persist longer and tissue lesions are more severe. In a recent study examining peritoneal myeloid populations during listerial infection, it was found that the frequencies of myeloid cells producing IL-12 and TNF-a were higher in mice genetically deficient in gd T cellsref [33•]. In vivo dye tracking revealed that most of the inflammatory monocytes responding to the listeria infection differentiated into tissue macrophages in situ. The monocytes harvested from mice lacking gd T cells were defective in this maturation, suggesting that ?? T cells promote differentiation along the monocyte and macrophage lineage. gd T cells also have a part in macrophage recruitment, not only in infectious inflammation but also during the inflammatory response that accompanies wound healing. Skin gd T cells, already known to recognize keratinocytesref [34] and to regulate keratinocyte proliferation after woundingref [35•], were also shown to induce hyaluronan production by epithelial cells and its subsequent deposition in the extracellular matrix, an essential part of the repair processref [36•]. Hyaluronan is then involved in recruiting macrophages to the wound, so that skin gd T cells are indirectly responsible for this recruitment. However, in listeriosis, gd T cells have been found to control the production of MCP1 in the liverref [37], so there might be more than one mechanism by which gd T cells direct macrophage recruitment during inflammation.
There is also a long-standing hypothesis that gd T cells terminate
macrophage responses once pathogen clearance has
been accomplished. A comparison of peritoneal
macrophages from normal and Listeria-infected
mice for lymphocyte binding in vitro revealed
selective, TCR-dependent interactions with one
splenic gd T cell
subset, Vg1+
cells, by the Listeria-activated macrophagesref
[38]. Activation of the gd
T cells was not required for binding but activated
cells were cytotoxic for the Listeria-induced
macrophages. The ability of Vg1+
cells to bind macrophages was found to be dependent
upon Fas–FasL interactions, and blocking of FasL and
TCR together prevented macrophage killingref
[39•]. Likewise, in an experimental model of
autoimmune encephalomyelitis, gd
T cells appeared to regulate inflammation in the
central nervous system by a FasL-dependent
mechanism, although in this case the targets were
IFN-gproducing
encephalitogenic T cellsref1,
ref2
[40 and 41]. This is not surprising because gd T cells tend to express
FasL at high levels and have been implicated
previously in FasL-dependent killing. However, these
studies confirm the proposed role of gd T cells in the resolution
of inflammation, and in macrophage elimination in
particular. The studies on gd
T cell-dependent macrophage lysis reemphasize the
functional specialization of TCR-defined gd T cell subsets, with an
additional twist: Vg1+
cells involved in early versus late stages of Listeria-induced
host responses appear to belong to nonoverlapping
populations with different functional propertiesref
[42••]. It remains to be established whether these
differences reflect a predetermined heterogeneity
or, as suggested by the authors, plasticity in
response to environmental influences. Finally,
overall cell counts in thymus and spleen of
genetically Vg1-deficient
mice were increased 1.5-fold, consistent with the
idea that Vg1+
?? T cells kill leukocytes.
A crosstalk with DCs which has
consequences : there is now ample evidence
that gd T cells and DCs
exert regulatory influences on each other.
Cytokine-mediated communications involving
skin-derived gd T cells
and Langerhans cellsref
[43] were demonstrated early, and subsequently it
was shown that human gd
T cells can induce DC maturation [44], via CD1ref
[45]. More recent studies show that such
interactions are bidirectionalref1,
ref2
[46• and 47•]. Thus, coculture with Vg9Vd2+
human gd T cells
activated with IPP or pamidronate resulted in the
functional activation of immature DCs, including
increased expression of CD86 and MHC class I. This
effect was mediated mostly by lymphocyte-derived
TNF-a and IFN-g. A similar study showed
that DC maturation induced by lipopolysaccharide was
enhanced by activated gd
T cells [48]. In turn, activation of the ?? T cells
depended on immature DCs, and activation with
pamidronate, but not IPP, required cell–cell contactref
[47•]. Activation of human ?? T cells by
polyinosinic-polycytidylic acid, a ligand for TLR3,
also depends on DCs and appears to be mediated by
type 1 IFNsref
[49]. It is quite clear that such interactions are,
again, defined within subsets of gd T cells. In mice
intranasally infected with Bacillus Calmette–Guerin
(BCG), Vg1+
cells are recruited to the lung, where they promote
the development of cytotoxic CD8+ T cellsref
[50]. In vitro, the same cells are induced
by DCs infected with BCG to express CD69, to produce
IFN-g and to cytotoxic
activityref
[46•]. This functional induction was mediated by
DC-derived IL-12 and did not require cognate
interactions between gd
T cells and DCs, or even cell–cell contact. Vg1+ cells, in
turn, produced IFN-g,
which increased IL-12 production by the BCG-infected
DCs. Importantly, Vg1+
cells induced the BCG-infected DCs to prime a
stronger antimycobacterial response of CD8+
T cells. On the basis of this evidence, the authors
suggest that the interaction of ?? T cells and DCs
might be employed as an immune adjuvant when trying
to induce CD8 T cell immunity by vaccination. It
seems unlikely, however, that the interactions
between DCs and gd T
cells only serve in the development of the adaptive
immune response because activated DCs would also
influence ‘innate lymphocytes’ such as NK T cells. A
recent study examining the requirements of gd T cells capable of
suppressing AHR suggests such innate pathwaysref
[51•]. Here, AHR-suppressive gd
T cells required functional induction, which could
be provided by conventional immunization with
ovalbumin plus adjuvant, designed to activate APCs
and prime gd T cells.
This was surprising because, although the
suppressive gd T cells
belong to a distinct subset (Vg4+
cells), they are not antigen specific, and they
suppress AHR in a manner independent of gd T cellsref
[52]. Perhaps, in this case, crosstalk between DCs
and gd T cells prepares
the latter to carry out their innate biological
function. Once prepared, very small numbers of the Vg4+ cells can
alter the physiological properties of the entire
lung. For this to occur, their responses must be
amplified and propagated. Neuronal mechanisms come
to mind but the innate immune system is also well
known for its ability to amplify local responses via
soluble mediators, most notably, perhaps, the
activation pathways for complement. Specific
complement components, the anaphylatoxins, are
generated and have important roles in the innate
responses to wounding and airway stimulationref1, ref2
[53 and 54], and a connection of gd T cell responses with
these ubiquitous mediators potentially could provide
the required amplification.
Concluding remarks : although many studies now
suggest that gd T cells
have a prominent role in the innate response,
information about underlying mechanisms remains
scarce. It is unclear at what developmental stage
subpopulations acquire their distinctive functional
potential, and it is unresolved how these
specialized cells, which tend to occur in very small
numbers, might achieve tissue-wide effects. Some of
the innate functions of gd
T cells, such as their newly discovered ability to
present antigen, provide obvious connections with
the adaptive immune response. However, the embedment
of gd T cells in the
innate immune response eventually might prove to be
their most distinguishing feature. Where will we go
from here? The development of a general theory of
ligand recognition through the gd
TCR remains the most important challenge. The newly
discovered APC function of gd
T cells is also likely to attract much interest.
Perhaps it will be found that gd
T cells are able to use their TCR for antigen
sampling, in a manner similar to B lymphocytes. The
correlations between TCR-V? expression and function
represent another obvious challenge. Here, it
remains to be determined whether this reflects a
relationship between specificity and (the
development of) function, or something else
entirely. Finally, investigations of the
interactions between gd
T cells and other leukocytes, DC in particular, is
likely to intensify and ultimately help to define
the position and role of gd
T cells in the immune system.
Update : small, non-peptide ‘antigens’ that activate
human Vg9Vd2 T cells can be divided
into 3 general classes: pyrophosphomonoesters, such
as IPP, nitrogen-containing biphosphonates (N-BPs),
and alkylamines. A study recently published shows
that alkylamines are inhibitors of farnesyl
diphosphate synthase (an enzyme in the mevalonate
pathway) and activate Vg9Vd2 T cells indirectly by
causing the intracellular accumulation of IPPref
[55••]. Earlier, the same group and others had shown
that N-BPs activate human gd
T cells by essentially the same mechanismref1,
ref2
[56 and 57]. These findings leave
pyrophosphomonoesters as the only non-peptide
‘antigens’ that still might be true Vg9Vd2
T-cell agonists.
See also activation
of
naive gd T
lymphocytes
See also immunodeficiency
with
gd T cell expansion and
autoimmunity
Experimental animal models
:
... or ...
+ the ATP-dependent chromatin remodeller chromodomain helicase DNA binding protein 4 (CHD4) / Mi-2b — which was previously thought to be a negative regulator of gene expression — is a positive regulator of CD4 expression associating directly with the Cd4 proximal enhancer through its interactions with the E-box-binding protein TCF12 / HEBref
RA-RO+,
TcRablow + cCD3deg)
, and the lymphotoxin (LT)
receptor (LTR)ref.
RA+RO-49d/VLA-4-152/CTLA-4-154/40L/gp39-,
TcRabhi). SLAP links the
E3 ligase activity of c-Cbl to the TCRz, allowing for stage-specific
regulation of TCR expression via ubiquitination and
degradation, preventing the accumulation of fully
assembled recycling TCR complexesref.
continue to proliferate and differentiate, while the
others - i.e. those with no or strong TcR signals -
undergo programmed
cell
death (PCD)in
the
thymus within 3 or 4 days of their last divisionref1,
ref2,
ref3,
ref4,
ref5,
ref6.
T cells with high-affinity class II reactive ab TCRs are functional, but there
is an affinity threshold above which an increase in
affinity does not result in significant enhancement of ab T cell activationref.
Calcineurin
regulatory
subunit (Cnb1) is essentialref.
) : T cells
with a high-affinity TcR for self-MHC (alone or
combined with a thymus-derived self-peptide) are
(negative selection)ref1,
ref2,
ref3
... :
(in a Bim-,
Bak1-,
Bax-
and LIGHT / TL5-dependent
manner) is triggered
by LT-b
or TNF-b / LT-a signaling via LTbRref
and activation of theautoimmune
regulator (AIRE), whose loss-of-function mutations
cause APECED
and Omenn
syndrome).
AIRE
contains 2 plant homeodomains (PHDs) which have
recently been shown in other proteins to facilitate
polyubiquitylation of target proteins : PHD1 pof AIRE
has E3 ligate activity, which is abolished by common
disease-causing mutations. By contrast, PHD2 is
responsible for transcriptional repression. It remains
to be determined whether the E3 ligase activity modifies
proteins in the AIRE-containing transcriptional complex
or has an independent effectref
mechanisms. ,
mature T lymphocytes never reenter the thymus cortex.
),
and
20-30% of lymphocytes in spleen (in TCZ
of
PALS).
, IL-15, IL-15Ra,
Fyn,
Ets1,
Itk,
IRF1,
GM-CSFR, CD132
/ gc CD1D, sTNF-b
and LT-b
to become a :
: the CD1D specificity relies on
the TcRa-chain, which is
normally acquired by developing thymocytes at the DP
stage. Inhibitory NK receptors probably prevent
unchecked autorectivity for CD1D. As the expression
of CD161
/
KLRB1 / NKR-P1A is acquired on maturity after
activation in extrathymic tissues, they are referred
just as Va24+
invariant T cells (Va24i
oriNKT or NKTinv).
Expression of Aire
in thymic medullary epithelial cells (MECs) is
required for development of iNKT cells, suggesting a
role for iNKT cells in APS1ref.
They are less frequent in humans than are the Va14i T cells in mice.
They locate in thymus (where they are unable to
respond due to interaction with the thymic stroma),
peripheral blood (4% all ab
T-cells), spleen (3%), liver (30÷50%;
LFA-1-dependent migration), bone
marrow, lungs (CCL2-dependent
migration) and peripheral lymph
nodes (0.5%). They all express CD122 / IL-2Rb
: they are considered to be innate lymphocytes
and killer
cells. 4 subsets exist :
than DN ones, but are less
able to induce expression of perforin
after exposure to cytokines.. CD8 acts as a coreceptor
for CD1D. : although this is an
attractive hypothesis, the affinity of CD1D for
CD8ab misured by
biacore is several orders of magnitude lower
than the affinity of classical MHC class I
molecules for CD8ab :
further it is about the same as for CD8aa. (with the possible exception of
psoriasis and the
hyperplastic thymus in myasthenia
gravis). They can be expanded very
rapidly in vitro in presence of a-Gal-Cer, APCs+IL-2 or IL-7+IL-15. Only
about 50% of the iNKT cells in the peripheral blood
are CD4+ cellsref
: they preferentially produce IL-4 and IL-13ref1,
ref2,
ref3,
ref4.
They can be identified with CD1d tetramers loaded
with a-Gal-Cer,
monoclonal antibody 6B11 (which specifically
recognizes the CDR3 region of the V24-J18 T-cell
receptor of human iNKT cellsref)
(?), liver, spleen and bone
marrow (?). 2 subsets exist : and bone
marrow, compared with the thymus and liver.. CD8 acts as a coreceptor
for CD1D. (?), liver,spleen and bone
marrow...
, CD86,
ZAP70,
RasGRP,
Vav1,
Csk,
Itk,
GADS,
Id3,
GATA3ref
and ERK1
to become a :
RA+69+NKG2D-,
TcRabhi)RO+62L
/ MEL-14+69+90 /
Thy-1+, x+h+,
TLR3+9+ref
TcRabhi).
They produce low levels of all the cytokine kinds
produced by Th1, Th2 and TReg,
but expecially IL-2, IL-4 and
IFN-g. See also activation
of
naive CD4+ Th0
lymphocytes. ... to
become a ....
RBlow103
/ aE
integrin+127low152
/
CTLA-4+ CCR4+CCR8+TNFRSF18
/
GITR+TR1
lymphocyte (10% of total CD4+
T lymphocytes). Differential regulatory capacities
of the CD62L
/ L-selectinhi and CD62L
/ L-selectinlo subsets in
vivo reflect differences in homing
properties, rather than suppressor potential per
se. They secrete : (=> control of
inflammatory reactions).
signaling, but that interleukin 2 was essential for
the survival of mature Foxp3+ Treg
cells in vivoref1,
ref2.
In vitro, they fail to produce IL-2 after TcR
stimulation, suppress both CD4+ and CD8+
T cell responses (even to an unrelated Ag !),
but require TcR stimulation for induction of their
suppressor function via mechanism depending on the
location and context of the inflammatory response
that they are called upon to suppress :
- and TGF-b1-dependent mechanism-, IL-10- and TGF-b1-independent mechanism that
suppress IL-2 and IFN-g production in
the responder population. production and the
proliferation of the CD25-
responder T cells
production, which in turns upregulates
transcription of the gene encoding indoleamine
2,3-dioxygenase
(IDO) in DCs, the
enzyme that catalyses the initial step of
tryptophan degradation, linked with
tolerance induction during pregnancy,
transplantation and autoimmunityref. Ttryptophan
metabolites in the kynurenine pathway, such
as 3-hydroxyanthranilic and quinolinic
acids, will induce the selective
Fas-independent apoptosis in vitro and
in vitro of murine thymocytes and Th1 but not Th2 cells, in a fashion
qualitatively similar to dexamethasoneref signal in
the thymus for development (and also in vitro
for expansion), but can be maintained for long times
in the periphery by other cytokines, such as IL-4, the
production of which is dependent on co-stimulatory
signals. They are resistant in vivo and in
vitro to Fas-induced activation-induced
cell
death (AICD), including clonal deletion
following viral SAg-induced
activation : even if sensitivity to apoptosis can be
increased by contact with IL-2-producing CD4+25-
T cells in vitro, this resistance may
be important in maintaining a permanent population
of regulatory T cells that can control and
eventually suppress autoreactive T cells or harmful
T cells activated during normal immune responses. By
allowing the persistence of parasites, IL-10
secreting Treg cells might benefit the
host by maintaining protective immunity.
RC-T
lymphocyte. Although they are less potent on a
cell-for-cell basis, they contribute to at least
an equal extent because of their greater numerical
representation (90%) in the CD4+ T-cell
population. expression
has been proposed as a new surface markerref
: it binds to N-terminal part of SIVA
/
CD27BP, a pro-apoptotic proteinref.
(=> down-regulates
CD80and
CD86)RA+RBlowRO-152 /
CTLA-4+LIGHT+
that produces :
(autocrine
stimulation), which inhibits Th1 differentiation, stimulates
Th2 differentiation and
suppresses in vitro proliferation and IFN-g secretion by
CD8+ T cells. (so IL-10
independent) :
translocation inhibitors (e.g. BAY)-/-
BMDC -producing.
Suppressive
activity requires cell-cell contact and is APC-independent
and Ag-independent. When transferred into naive
wild-type mice they can suppress previously primed
immune response
in in
vitro co-culture assay of naive
responder cells and suppressor cells. It does not
show any involvement of inhibitory cytokines such
as IL-10 or TGF-ß. in in
vivo transfer of small numbers of naive
T cells to severely lymphopenic hosts, which then
generate exaggerated immune responses resulting in
immune pathology. Lymphopenia is invariably
associated not only with homeostatic expansion of
the remaining (or adoptively transferred)
lymphocyte populations in response to endogenous
peptide–MHC ligands and IL-7, but also with immune
reactivity to both self and foreign determinants
that would not normally be apparent in
T-cell-replete hosts. Those T lymphocytes with
higher avidity for self-peptide-MHC molecules (CD5+)
have increased competitive (and hence suppressive)
potential. Anyway IL-7-/- mice have a
robust regulatory FOXP3+ CD4+
T cell compartment that prevents T-cell mediated
disease. Regulatory FOXP3+ CD4+CD25-
T cell population has the potential to restore a
functional CD4+CD25+ T cell
compartment through an IL-7 independent pathwayref., IRF1,
Id3,
ERK1,
ZAP70,
RasGRP,
Vav1,
Itk
and GADS
to become a :
RA+57+62L /
MEL-14+69+,
x+h+,
BLT1
/ P2Y7lo, NKG2D-S-,
NKG2D-L-,
TcRabhi). See
also activation
of
naive CTLs. (with
or without synergizing by IFN-a)
to become a ...
immunity. Veto activity was
defined in 1980 by Millerref
as the capacity to specifically suppress
cytotoxic T-cell precursors (CTL-p) directed
against antigens of the veto cells themselves but
not against third-party antigens.
Interestingly, it has been shown that some of the
most potent veto cells are of T-cell origin and, in
particular, a very strong veto activity was
documented for CD8+ CTL lines or clonesref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7.
The specificity of the veto effect mediated by CTL
clones was shown by several studies to be unrelated
to their TcR specificityref1,
ref2,
ref3.
The suppression of effector CTL-p directed against
the veto cells is both antigen specific and MHC
restricted, resulting from the unidirectional
recognition of the veto cell by the responding CTLs,
but not vice versaref.
Furthermore, it has been shown that this suppression
is mediated by apoptosisref1,
ref2
and that coexpression of both CD8 and Fas ligand
(FasL) is a prerequisite for the veto
reactivity of the CTLsref.
Veto CTLs induce apoptosis in the effector T cells
by a Fas-FasL–mediated mechanism. Upon engagement
between the TCR of the effector cell and class I
(MHC I) of the veto cell, the effector cell is
activated and Fas is up-regulated, allowing for the
FasL on the veto CTL to induce apoptosis. However,
inhibitors such as FLIP protect the activated
effector T cell. The high affinity afforded by the
interaction between CD8 on the veto cell and class I
(MHCIa3) on the effector
cell enables prolonged association until FLIP is
down-regulated and apoptosis can take place.
,
which is congenitally athymic, or athymic radiation chimeras
reconstituted with normal hemopoietic precursors. These mice
initially have no T cells (and are often used as recipients
of grafts of human cells and tissues for experiments), but
as they age, one can find fully functional TcRgd+ T cells. No one yet
knows where these cells arise. Bone
marrow
and the appendix (the only 2 other sites where RAG is only
known to be expressed) may be the sites of extrathymic T
cell development. It is likely that a fourth (or more)
site is where extrathymic T cell development occurs. There
is no evidence of T cell development in the blood,
spleen or lymph
nodes.
, which maintains the
activity of anti-apoptotic (anti-death) pathways.
However, the limiting amounts of IL-7 that are available
relative to the large number of T cells suggests that a
mechanism must exist that enables cells to compete
successfully for this resource without risking the loss
of antigenic diversity as represented by the whole T
cell population. IL-7 ligation induces down-regulation
of IL-7Ra via activation of
the transcriptional repressor growth
factor
independent 1 (GFI1)ref–mediated survival and T cell
receptor–dependent activation of transcription factor NF-kB and the kinase Jnk. In effector T
cells, TAK1 was dispensable for T cell receptor–dependent
NF-kB activation and cytokine
production, but was important for proliferation and
activation of the kinase p38 in response to IL-2, IL-7 and
IL-15. Thus, TAK1 is essential for the integration of T cell
receptor and cytokine signals to regulate the development,
survival and function of T cellsref.
.
The major part of involved proteins arise from duplication and
divergence of a Ig precursor gene, coding for a 110 amino
acids-long p12Ig
domain :
so the actual molecules contain a natural multiple of such
domain. The response induced upon antigen binding doesn't
depend on antigen structure.See also Database of Sequences of
proteins of Immunological Interest. via IRF1. They
consist of 6 pockets termed A to F : B, C, D, and E pockets
are placed at the a-helix-b-fold
hunction, while A and F pockets are placed between a-helices.
In Golgi apparatus the N-terminal oligosaccharide is
further processed.
or autoimmunity (including tumor immunity)), including
epitopes created by post-translational protein splicing
(e.g. FGF5 peptide consisting of 5 amino-terminal amino
acids and 4 carboxy-terminal amino acidsref))
: b1, b2 and b5 subunits are
amino-terminal nucleophile (NTN) hydrolases with Thr in
active sites. During de novo assembly induced by
IFN-g they are totally or partially replaced
by the immunosubunits:b9
/ large multifunctional protease 2 (LMP2),
is incorporated into newly synthetised proteasomes as b1i (in place of d), b7 / LMP7
as b5i
(in place of X), and b10 / MECL-1
as b2i (in
place of Z) to produce so-called immunoproteasomes
(their incorporation is cooperative, e g. b1i before b2i). Even TNF-a
can up-regulate the LMP2 gene, either alone or
synergistically with IFN-g.
The immunosubunits alter whole proteasome stucture and
allow higher efficiency in substrate channelling within
the proteasome and cleavage specificity, thereby
changing both the quality and the quantity of peptide
products. IFN-g-induced
coincident biosynthesis of proteasome maturation
protein (POMP) and LMP7 and their direct interaction
essentially accelerate immunoproteasome biogenesis
compared with constitutive 20S proteasome assembly. The
dynamics of this process is determined by rapid LMP7
activation and the immediate LMP7-dependent degradation of
POMP. Silencing of POMP expression impairs recruitment of
both b5 subunits
into the proteasome complex, resulting in decreased
proteasome activity, reduced MHC class I surface
expression, and induction of apoptosis. Furthermore,
immunoproteasomes exhibit a considerably shortened
half-life, compared with constitutive proteasomes,
allowing cells to return rapidly to a normal situation
once immunoproteasome function is no longer requiredref. induces the
synthesis of a 11S regulator / PA28 (made up of PA28a and PA28b in a a3b4-arranged
complex plus PA28g), enhancing peptide
presentation in a immunosubunits-independent manner. In
fact in vivo the rate-limiting step in protein
degradation is not the width of the gate but substrate
binding to the 19S regulator, as well as its channelling
into the 20S core. Anyway because product exit from the
proteasome occurs by diffusion, the width of the gate will
determine the diffusion rate : in a situation in which a
gate is not fully open, the retention time of a processing
intermediate in the catalytic chamber will be increased
and the exit of larger peptide products will be hindered
(just like in a food-processor, the length of time that
the ingredients are processed affects the quality of the
product !). The proteasome generates peptides ranging from
3 to 22 amino acids in length, but a relatively
larger percentage of antigenic peptides are generated by
immunoproteasomes as precursor peptides of 10-12
residues. Because some processed peptides have
residues close to their amino termini (Pro, for example)
that impair their TAP-mediated
transport
into the ER, by creating products with an amino-terminal
extension the proteasome allows these epitopes to pass
unhindered into the ER, where they can be trimmed to the
optimum size for binding to MHC class I groove by the IFN-g-inducible
ER
aminopeptidase involved in antigen processing (ERAAP)
(in some rare cases, cytosolic
trimming might also take place). Loss of ERAAP
disrupts the generation of naturally processed peptides in
the ER, decreases the stability of peptide–MHC class I
complexes and diminishes CD8+ T cell responses.
Thus, trimming of antigenic peptides by ERAAP in the ER is
essential for the generation of the normal repertoire of
processed peptidesref.
,
representing an important mechanism to control reactivity
of autoreactive CD8+ T cells that escape thymic
delection.
lumen by the transporter of antigen peptides (TAP)
complex located on RER membrane : TAP complex is an
ATP-binding cassette consisting of 4 tapasin
/ TAPBP / / TAPA
glycoproteins assembled with each TAP1
/ TAP2
heterodimer (all genes are up-regulated by IFN-g).
,
a transmembrane protein which binds to the lumenal face;]
in the ER membrane. Calreticulin binding depends on the
glucose residue in the N-linked glycan and is
independent of MHC class I molecule conformation (free MHC
class I heavy chains, empty MHC class I-b2-microglobulin
heterodimers and peptide-loaded MHC class I complexes)
providing support for the hypothesis that, by binding
monoglucosylated N-linked glycans, calreticulin
cannot determine the conformation of the proteinref in the ER
lumen. is
an Hsp90 that acts as an ER marker. Tapasin brings the class I
MHC molecule close to the remaining components of the TAP
complex, allowing the fomer to acquire the antigenic peptide
from the latter. Assembly of this compex is associated with
formation of a disulfide bond between tapasin and ERp57. ERp57
and BiP then dissociate from the now stable class I MHC
molecule. The capacity of MHC class I /b2m/peptide
complexes
to form dimers may be important during Ag loading.
downregulates MHC class I translocation
impairs b2m
binding to MHC class I.
. from the cell body
and dendrites. Lesioned sciatic motoneurons in b2m or TAP1-null mutant mice
show more extensive synaptic detachments than those in
wild-type animals. This surplus removal of synapses is
entirely directed toward inhibitory synapses assembled in
clusters. In parallel, a significantly smaller population of
motoneurons reinnervates the distal stump of the transected
sciatic nerve in mutants. MHC I molecules, which traditionally
have been linked with immunological mechanisms, are thus
crucial for a selective maintenance of synapses during the
synaptic removal process in neurons after lesion, and the lack
of MHC I expression may impede the ability of neurons to
regenerate axonsref.
,
phagocytosis or macropinocytosis) => occurred => direct
endosomal loading of still available
MHC class I molecules. Latex beads labelled with
fluorescent ovalbumin were phagocytosed and
fluorescence could be detected in the cytoplasm,
indicating that exogenous proteins are
retro-translocated into the cytoplasm for
degradation by proteasomes. Indeed, proteasomes
and polyubiquitylated proteins are associated with
the cytoplasmic side of the phagosome. The
cross-presentation of peptide-MHC class I
complexes is partially inhibited by treatment with
brefeldin-A (which blocks the secretory pathway),
whereas conventional presentation is totally
inhibited, supporting the idea that phagosomes are
the source of the MHC class I complexes in the
brefeldin-A-treated cellsref1,
ref2.
Various ER-resident proteins (e.g.
glucose-6-phosphatase, TAP, tapasin, and
calreticulin) are detectable on early phagosomes
from immature DCs : functional assays showed that
pohagosomes are a site of TAP-dependent peptide
loading onto MHC class I molecules, leading to
T-cell stimulationref.
Exogenously added soluble US6
inhibits cross-presentation, showing that the TAP
inhibition occurred in a location where
internalized proteins have access to ER componentsref.
The fusion of endoplasmic reticulum membrane with
nascent phagosomes allows intersection of the
endosomal system with the endoplasmic reticulum,
the classical site of MHC class I peptide loading,
and may reconcile the seemingly conflicting
evidence indicating both of these sites are
crucial in cross-presentationref
induces cross-priming by a mechanism dependent
on type I interferons, independent of CD4+
T cell help or CD40/CD40L interaction, and
involves direct stimulation of DCs), which binds to gp96,
HSP70, and HSP90. HSP70 is
also able to translocate across cellular
membranes and gains cytoplasmic entry, which
allows the protein Ags to be processed by
cytoplasmic proteasomes, and subsequently, to
enter the MHC class I pathway.
pathway => => classical
MHC class I processing. E.g. : : in the ER lumen the A1
chain is released from the rest of the toxin, so
that it can be recognized as a misfolded
protein. (RTA)..
If primed by LPS, also immature resting CD4-8-
DCs (migrated from marginal zone to T-cell area of
the spleen) become cross-presenting, although with far
poorer capacity. In vitro they are more
effective cross-presenters than mature DCs (that have
lost phagocytic ability), Mf
and B cells.
and if helper T cells are available.
and peripheral
CD8+ CTL tolerance (cross-tolerance).
The cross-tolerizing APC is still unknown. Such
cross-presentation induces proliferation of naive CD8+
CTLs, but ultimately leads to their deletion) and
barbus (Barbus
intermedius).|
|
|
|
| MHC locus | HLA-E
(associated with class I 6.2-kB HindIII
fragment, 5 alleles) is expressed in all cells but found
on cell surface only in some but not all activated
T
cellsref1,
ref2,
ref3,
ref4,
and on the surface of extravillous trophoblast that
has invaded the maternal deciduaref
(syncytiotrophoblast, villous mesenchymal cells,
extravillous trophoblast and several decidual cell
types, but staining for HLA-E appeared to be confined
primarily to the cytoplasmref).
HLA-E
is structurally homologous to classical MHC class I
proteinsref1,
ref2,
also requiring association with peptide for cell
surface expression. In contrast to MHC class I,
however, HLA-E only binds a restricted set of nonamer
peptides that are primarily derived from the leader
sequences of class Ia
(HLA-A, -B, -C) and -G moleculesref1,
ref2,
ref3,
ref4,
though peptides derived from other cellularref
and viralref1,
ref2
sources have been identified. More recently, HLA-E has
also been implicated in the presentation of
self-peptides and bacterial antigens to T cells,
although the role of these T cells in immune responses
remains to be establishedref1,
ref2,
ref3,
ref4.
The generation of the MHC signal peptide-derived
epitopes binding to HLA-E does not follow the
"conventional" antigen-processing pathway described
above. During biosynthesis of the MHC class I
pre-protein and its translocation into the ER lumen,
the signal sequence is cleaved by signal peptidase and
subsequently processed by signal
peptide
peptidase (SPP) / HM13ref1,
ref2(20,
21).
This second cut occurs in the hydrophobic
membrane-spanning region, allowing the release of an
14 residue-long N-terminal signal peptide fragment
into the cytosol. Proteasomal activity is then
required to trim the extended peptide fragment
liberated into the cytosolref,
consistent with the finding that C-terminal trimming
increases the efficiency of TAP transport and is
required for peptide binding to HLA-Eref
(20). Peptide entry into the cytosol is consistent
with the TAP dependency of HLA-E expression. The
epitope-containing fragment is then transported into
the ER lumen for loading onto newly synthesized HLA-Eref
(20). 2 nonsynonymous alleles of HLA-E are retained in
the human population, maintained through strong
balancing selection, distinguished by a single
sequence dimorphism at position 107: glycine (E*0101;
HLA-EG) or arginine (E*0103; HLA-ER)ref.
Biophysical studies have shown that both allelic and
peptide sequence differences have significant effects
on HLA-E solution stability, correlating with
differential cell surface expression levelsref.
E*0101 allele is significantly higher in patients with
recurrent spontaneous abortionref.
The expression of the Qa1–self-peptide complex on
antigen-activated T cells is a function of the
intermediate-avidity interaction between TcRs on
T cells and MHC–antigen-peptide complexes presented by
conventional APCs during the T-cell activationref.
The Qa1–self-peptide complexes, as surrogate
structures expressed on target T cells, are
recognized by the a/b T-cell receptors on regulatory CD8+ T
cellsand trigger the CD8+ T
cells to differentiate into effector cells. These
effector cells in turn down-regulate any activated
intermediate-avidity T cells expressing the same
Qa1–self-peptide complexes during the secondary
immune responseref.
It binds to CD94 included in either an inhibitory
(associated
with NKG2A or NKG2B) or activatory
(associated
to NKG2C or NKG2D) receptor on NK cells and
CD8+ T lymphocytes (although <5% of CD8
T cells express the receptor in a naive mouse,
its expression is upregulated upon specific
recognition of antigen). Similar to NK cells, most CD8
T cells that express high levels of CD94 co-express NKG2A, the inhibitory isoform. The
engagement of this receptor can lead to a blocking of
cytotoxicity. However, these receptors have also been
implicated in the cell survival of both NK and CD8 T
cells. The level of CD94 expression is inversely
correlated with the level of apoptosis in cultureref.
The concomitant presence of the appropriate HLA class
I alleles with leader sequence-derived peptides and
HLA-E heavy chain may not be sufficient to allow HLA-E
surface expression in tumor cell lines (e.g. only 23%
in osteosarcomas) as opposed to lymphoid cellsref. |
yes |
| HLA-F (associated with class I 5.4-kB Hind III fragment) is not expressed on cell surface other than extravillous trophoblast that has invaded the maternal deciduarefand has unknown function | yes | |
| HLA-G (associated with class I 6.0-kB Hind III fragment; 8 alleles; 6 isoforms from alternative RNA splicing) has a limited distribution on the cell surface on extraembryonic tissues (i.e., on extravillous trophoblast that has invaded the maternal deciduaref) and is thought to prevent killing of fetal cells : it is also expressed in many glioblastomas, preventing efficient priming of Tc-cells. In addition, soluble HLA-G isoforms have been detected in the serum of pregnant and nonpregnant women as well as men (produced by Sertoli cells, spermatocytes and spermatids). HLA-G is recognized by the inhibitory receptors KIR2DL4, LIR1 and LIR2 on NK cells. | yes | |
), virally infected cells (MICA
expression is also upregulated as a result of the
binding of Escherichia coli adhesin AfaE to
CD55 and by cells infected with Mycobacterium
tuberculosis) and a wide variety of carcinomas
: elements in their promoters are similar to HSP
genes and permit their up-regulation of them in
stressed and transformed cells. Expression of MICA
and MICB by DCs can also be induced by IFN-a.
Despite the presence of an MHC a3-like
domain,
they do not bind b2-microglobulin
(not required for folding, stability, or cell
surface expression) so their expression would not be
affected by the loss of b2-microglobulin,
which occurs in certain tumors. They have an
occluded peptide-binding groove, too small to allow
for the binding of anything larger than the
equivalent of a 3- or 4-residue peptide. This, plus
the polar character of the lining of the pocket and
the lack of any electron density not accounted for
by protein atoms in the structure, led to the
conclusion that they don't bind any peptide or other
small-molecule ligand. The platform and a3 domains are
joined through a flexible linker, allowing
considerable interdomain flexibility, a feature
unique among MHC class I proteins and homologs. They
are highly polymorphic (150 MICA alleles and 19 MICB
alleles known) and are broadly recognized by ...
for the
immune system. A 100-kb deletion
including the MICA gene has been reported in the
HLA-B48 (B*4801)-associated haplotype in East Asians
(Japanese, Koreans) and Angaite Amerindian community
in Paraguay (with the novel recombination haplotype
between this MIC null haplotype and HLA-B15,
HLA-B15-MICA-del-MICB*0107 N). Interestingly, this
MICA deletion is accompanied by a MICB null allele (a
premature stop codon), MICB0107N. Maybe the expression
of both MICA and MICB molecules is indispensable to
viability through a yet-to-be understood mutual
interaction in immune surveillance. |
no | |
| HFE
/ HLA-H (very similar to HLA-A) is
expressed in all tissues except brain. It does not
bind peptides but regulates the Tf-CD71 /
TfR binding : at least 11 isoforms exist.
Deficiency leads to hereditary
hemochromatosis. |
yes | |
| loci other chromosome 6 | (HHV-5
/
CMV-encoded) UL16 binding proteins
(ULBPs) / human retinoic acid early transcript 1
(RAET1) proteins (coded on chromosome 6q25,
outside the MHC region). They bind to the activating
receptor NKG2D on NK cells
and Vd1 gd
iIELs.
Pseudogenes :
Most of the RAET1 proteins, similar to the mouse Rae1
proteins, are attached to the plasma membrane with a
lipid linkage (despite RAET1E and RAET1G have
transmembrane domains) and have considerable sequence
diversity, ranging as low as 35% amino acid identity
in pairwise comparison, but all have a similar and
unique domain structure, consisting of 2 ectodomains
that are distantly related to the a1
and a2 domains
of MHC class I molecules, except that the site
corresponding to the MHC peptide-binding groove is
closed off, apparently preventing the binding of
peptides and other small molecules. Some of RAET1
proteins are expressed at marked levels by various
normal cells at the mRNA level, but cell-surface
expression by normal cells is low or has not been
documented : they are induced in distressed or
HCMV-infected cells |
? |
| CD1 family | yes | |
| endothelial protein C receptor (EPCR) | ? | |
| FcRn | yes | |
| MR1 / HLALS | ? | |
| Zn-a2-glycoprotein I does not bind peptides and promotes triglycerids catabolism. It does not bind b2-microglobulin. | no | |
| thymic leukemia (TL) antigen is a murine nonclassical class I molecule expressed abundantly on intestinal epithelial cells, monocytes, and dendritic cells, that, in contrast to other MHC class I molecules that bind CD8ab, preferentially binds CD8aa : this interaction modifies responses mediated by TCR recognition of antigen presented by distinct MHC moleculesref | ? |
glycoprotein, binds activating receptor NKG2D ligands ULBPs
and MICB, retaining them
in the cell and effectively masking NK-cell recognition]
(e.g. EBNA1, the dominant CD4+ T cell antigen
of latent HHV-4
/
EBV
infection. Lysosomal processing after autophagy may thus
contribute to MHC class II restricted surveillance of
long-lived endogenous antigens including nuclear proteins
relevant to diseaseref)
lumen by TAP, here MHC class II binds with higher affinity
the invariant
chain
(IC) / Ii / p33÷41CD74. Due to the
presence of trimerization region in the Ii, 3 molecules of abIi trimers form a supramolecular
complex of a nonamer, (abIi)3.
Aided by the presence of targeting sequence in the Ii, this
complex is then transported to the endocytic vesicles, where
selective Ii degradation by cathepsin S
occurs leaving only the Ii fragment class
II-associated invariant chain peptide (CLIP) attached
to the peptide-binding groove of the MHC class II molecule.
pH lowering in the late endosome or in the
phagolysosome (a.k.a. MHC class II containing
compartment (MIIC) / MHC II vesicles (CIIV) compartment)
removes HLA-DO heterodimer (a / DN ;
b)
inhibition on HLA-DM
heterodimer (a ; b),
which now can detach CLIP allowing the MHC class II molecule
to eventually bind a peptide from phagocytated material.
HLA-DO is expressed in B cells but not in epithelial cells.
MHC class II-bound peptides adopt an extended type II
polyproline conformation with a common periodicity,
such that residues at P1, P4, P6 and P9 point down into MHC
pockets, whereas P-1, P2, P5, P8, and P11 are solvent
exposed and point toward the TcR. This is in part due to the
extensive, and often conserved, interaction with the peptide
backbone. Naturally processed MHC class II-bound peptides
possess ragged amino and carboxy termini referred to as peptide-flanking
residues (PFRs) because they are outside the MHC
anchor residues (P1, P4, P6, and P9) but within the MHC
binding groove (e.g., P-2, P-1, P10, P11). P1 appears
to be important for peptide stability. In contrast, residues
at P10 and P11 are frequently removed by Ag processing. PFR
recognition is a common event characteristic of TcR
recognition of MHC class II:peptide complexes : invariably,
the PFRs at P-1 and P11 of all of the MHC class II:peptide
complexes solved to date are solvent exposed and accessible
to the TcR. Interestingly, PFRs are a unique and exclusive
feature of peptides bound to MHC class II molecules, in that
MHC class I-bound peptides are predominantly of fixed
length. 
and leprosydisease
systems,
it has been suggested that DQ molecules may play a role in
immunosuppression, as opposed to the helper function of DR
molecules. However, in many other systems, Ag-specific
DQ-restricted T cells can be found. and
most epithelial (including endothelial) cell types : TNF-a, IL-4
and IFN-g
co-up-regulate MHC class II, Ii and cathepsin S expression.
),
when
catabolized after overnight culture (involving polysaccharide
oxidation) and conventionally processed by APCs, can associate
with MHC class II molecules and induce CD4+ T-cell
responsesref.
These observations might explain why some polysaccharide
vaccines work so well and might provide new approaches to the
design of vaccines for infectious diseases. PS-A can direct
normal immune system development in the mouse. Reconstitution
of germ-free mice with the bacterial commensal Bacteroides
fragilis expanded T cell numbers and restored lymphoid
structures that would otherwise have developed abnormally.
Expression of PSA was sufficient and necessary for this
activity and also reestablished balance in Th1 and
Th2 cell cytokine responses, through presentation
of PSA by dendritic cells. The finding that a bacterial
product can implement such direct governance over the
mammalian immune system may explain how our microflora help
maintain pathogen immunity while preventing unwanted
inflammation and allergyref.
is a Bcl-2
ortholog that disrupts constitutive MHC class II expression
by inducing retention of MHC class II positive vesicles in
an abnormal perinuclear distribution.]
,
NF-Y and
X2BP/CREB
families to a compact series of conserved cis-acting
elements termed the S/W/Z, X1, X2, and Y boxes found 100-200 bp
upstream of all MHC class II genes. CIITA ubiquitination
enhances its association of CIITA with both MHC class II
transcription factors and the MHC class II promoter. Additional
promoter-binding factors such as Oct-2
modulate cell- and stage-specific expression of MHC class II.
Transcriptional activation of the CIITA gene occurs through the
action of 3 promoters in mice (pI, pIII, and pIV). Immediately
downstream of each promoter exists a unique exon 1 that is
spliced with the remaining shared exons to form 3 different
types of CIITA (I, III, and IV). 
rely
strictly on the B cell promoter pIII, whereas macrophages and
all other DCs depend on pIref
.
Such dangerous transpositions are limited by the
amino-terminal region of RAG1 and the carboxy-terminal region
of RAG2 (containing a GTP-binding domain), which inhibit the
capture of the target DNA after DNA cleavage. RAG-2 expression
is under the control of LEF-1, c-Myb and Pax-5. A
Runx-dependent intergenic silencer and an antisilencing
element that interact at a distance of 85 kilobases regulate
expression of RAG1 and RAG2 in developing CD4+8+
T lymphocytesref.
machinery (Ku70,
Ku80, DNA-PKCS
/ XRCC7, DNA
ligase
IV and XRCC4).
Every
germ-line V, D and J gene segment has upstream and downstream recombination
signal
sequences (RSSs) consisting of a conserved heptamer
andnonamer motif separated by a spacer of 12 or
23 bp. A pair of RSS with unlike spacers serves to direct a
single recombination reaction and to ensure assembly of a
biologically useful product. The first phase of V(D)J
recombination consists of recognition of a pair of RSSs,
synapsis of the 12- and 23-RSS, and cleavage at the
signal-coding borders. Nicks mediated by RAG proteins were
detectable only in gene segments associated with RSSs containing
12–base pair spacers but not in those containing 23–base pair
spacers. These data support a model of capture rather than
synapsis for pairwise RSS cleavage during V(D)J
recombinationref.
Both recognition and cleavage steps are mediated by RAG1 and
RAG2. The cleavage step produces 2 types of broken molecules
corresponding to V(D)J recombination intermediates : those with
coding ends and those with signal ends. As a consequence of the
cleavage mechanism, coding ends are covalently sealed to form a
DNA hairpin. In contrast, signal ends are almost always blunt
with no sequence loss or addition. The second phase involves the
processing and joining of DNA ends, and includes hairpin
opening, insertions and deletions at the open coding ends, and
formation of a circular signal-joint (sj) (ie the
excised interposed sequence) and a coding-joint (cj).
One feature unique to the processing of coding ends, and
observed at junctional sequences of joined coding segments, is
the addition of palindromic
(P) nucleotides. Such additions correspond to the gain of
several nucleotide complementary to the last few nucleotides of
a full-length segment. Addition of P nucleotides is thought to
reflect the mechanism whereby hairpin coding ends are opened.
Nicking by a single-strand specific endonuclease at a site
either 3' or 5' of the hairpin tip would produce P nucleotide
overhangs. The second phase of V(D)J recombination also depends
upon the function of ubiquitous factors that partecipate in DNA
NHEJ. Lymphocytes typically express only one functional antigen
receptor, a restriction contributed to by allelic exclusion. In
the offspring of a mouse generated by nuclear transfer using a
single donor B lymphocyte, all immunoglobulin alleles are
inherited as found in the donor lymphocyte. This donor cell had
2 rearranged Ig L chain alleles, both directing the synthesis of
light chains that could form functional antigen receptors, one
of which was autoreactive. Progeny mice carrying this
immunoglobulin light chain allele produced mature B cells, some
of which continued to express the autoreactive receptor but
required another rearrangement to rescue them from negative
selection. Such receptor editing failed to destroy expression of
one original light chain allele, thereby recreating dual
receptor expression on these surviving B cells. Autoreactive
antibodies in serum of mice and humans are due in part to such
'passenger' receptorsref.
.
while the z and h
chains each contain 3 ITAMs. Upon ligand binding 2 events
occur :
of Nck1. of ZAP70
and/or FYN. Further LCK directly phosphorylates and activates Itk,
which in turns activates PL-Cg1.
(see also canonical
and schematicT-cell
STP
[free registration required]). Within 1', small MHC:peptide
clusters form in the contact zone. It takes about
10 peptides to make a synapse. The suppressor
ot
TcR signalling 1 (Sts1) and 2 (Sts2) are
redundant negative regulators of TcR signallingref.
: functional and imaging
experiments indicate that in the plasma membrane of T
lymphocytes (whose formation is dependent on CD28
costimulation and regulated by WASp)
may play an important role in helping to form the
structure of the IS. Lipid raft proteins have a random
distribution during localized activation of the T-cell
receptorref.
By expressing GPI-linked FRET donor and acceptor
proteins in Jurkat T cells, it has been showed that
distribution of lipid rafts (identified by the
GPI-linked proteins) throughout the cell membrane is
not altered by activation with CD3-specific antibodyref dimers
(usually a disulfide linked ab
heterodimer, rarely an aa
homodimer: a
is required for surface expression of b) (a
domain) --- MHC I (non
polymorphic a3
domain (also a2
domain and b2-microglobulin ?)
(containing 4 extracellular Ig-like
domains termed D1-D4) homodimers (via
K318 and Q344 in the D4 domain) --- MHC II (b2 domain)
: localization in lipid rafts (see below) has a
fundamental importance for CD4 (but not for CD8)
signalling (and also for HIV-1 entry). Several of the CD4
ligands have been described as multimers, including
MHC II as a dimer of ab
heterodimers, the chemoattractant cytokine IL-16 as a
homotetramer, and HIV-1 gp160 as a trimer., with both CD4 and CD8a forming similar "zinc clasp"
cores despite having little sequence similarity in their
cytoplasmic regionsref
and the immune system utilize
specific molecular recognition events between discrete cells,
cell:cell adhesion, positional stability, and directed
secretion for communication to fulfill their respective
functions. Both systems have evolved highly sophisticated
forms of information storage. In the immune system, the
synapse functions to provide specificity to the action of
otherwise nonspecific soluble agents through confinement to
the synaptic cleft and to coordinate cell migration and
antigen recognition during induction of the immune response. A
critical difference in the functional context of the neural
and immunological synapses is in the basic wiring of the
systems. The CNS is to a great extent hard-wired and
retains precise connectivity patterns throughout adult life,
with neurons projecting long axonal processes that form
synapses on complex dendritic trees of other neurons that may
be quite distant from the cell nucleus. Whereas CNS synapses
may be formed and pruned back in the adult, the long dendritic
and axonal processes anchor the cell bodies and prevent cell
migration. Thus, the CNS synapse is an "action at a distance"
junction, in relation to the nucleus where transcription takes
place. Therefore, most functions of CNS synapses may be
considered "postnuclear" in that they are carried out without
a
requirement for immediate transcriptional regulation,
although synaptic stimulation can lead to transcriptional
changes in the long term. CNS synapses can alter their
efficacy by processes such as receptor clustering by scaffold
proteins. Synapse-forming neurons are terminally
differentiated. In contrast, the immune system operates
through rapidly migrating T cells and their partners, the
dendritic cells (DCs), that congregate in tissues like lymph
nodes. This is essential to the operation of the immune system
because each T cell expresses a differente antigen specificity
and the point at which an antigen will enter the body to
become associated with a DC is not predictable. So it is
essential that T cells and DCs congregate and make many random
contacts to possibly find a match and form a synapse.
Migrating T cells assume morphologies similar to the growth
cones of neurons but move at least 50 times faster. Thus, the
T cell and DC cover greater distances than neurons in search
of foreign antigens, but when the synapse is formed it is
immediately proximal to the transcriptional machinery in the
nucleus. Whereas adhesion in the immune system is integrin
mediated, cadherins are believed to function in an analogous
capacity at the CNS synapse.
, Btk) and TFs
(Oct-2, EBF, PAX5
/ BSAP, GATA2).
If
no productive rearrangements occur, the B cell dies by apoptosis. Every V gene has
its own promoter, leading sequence and intron : the intron is
then eliminated in RNA splicing. Immunoglobulin heavy chain
rearrangement (VH-to-DJH) occurs only in
B cells, as methylation of lysine 9 on histone H3 (H3-K9)
inhibits it in other lineages : Pax5
/ BSAP, a transcription factor required for B cell
commitment, is necessary and sufficient for the removal of
H3-K9 methylation in the VH locusref.
The D genes may be translated in every of the 3 reading frames
(although 2 are preferred) and up to lenghts depending on the
resulting CDR3. TdT may add up to 15 random N nucleotides
in N regions, i.e. between between V and D
and/or D and J in the CDR3 of the H chain, which bind up to
50% of amino acids in the epitope. P-nucleotideaddition
consists
in cleaving the hairpin loop at the DNA ends to result in new
sequences in the junction region. 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 27A 27B 27C 27D 27E 27F 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 95A 95B 95C 95D 95E 95F 96 97 98 99 100 101 102 103 104 105 106 106A 107 108 109
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 35A 35B 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 52A 52B 52C 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 82A 82B 82C 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 100A 100B 100C 100D 100E 100F 100G 100H 100I 100J 100K 101 102 103 104 105 106 107 108 109 110 111 112 113
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 30A 30B 30C 30D 30E 30F 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 95A 95B 95C 95D 95E 95F 96 97 98 99 100 101 102 103 104 105 106 106A 107 108 109
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 31A 31B 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 52A 52B 52C 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 82A 82B 82C 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 100A 100B 100C 100D 100E 100F 100G 100H 100I 100J 100K 101 102 103 104 105 106 107 108 109 110 111 112 113CDRs can be placed on the numbering scheme according to 4 different definitions :
| CDR | Kabat | AbM | Chothia | Contact |
|---|---|---|---|---|
| L1 | L24--L34 | L24--L34 | L24--L34 | L30--L36 |
| L2 | L50--L56 | L50--L56 | L50--L56 | L46--L55 |
| L3 | L89--L97 | L89--L97 | L89--L97 | L89--L96 |
| H1 | H31--H35B (on Kabat's numbering scheme) |
H26--H35B | H26--H32..34 | H30--H35B |
| H1 | H31--H35 (on Chothia's numbering scheme) |
H26--H35 | H26--H32 | H30--H35 |
| H2 | H50--H65 | H50--H58 | H52--H56 | H47--H58 |
| H3 | H95--H102 | H95--H102 | H95--H102 | H93--H101 |
|
|
|
|
|
|
| CDR-L1 | approx residue 24 | almost always a Cys | almost always a Trp. Typically Trp-Tyr-Gln, but also, Trp-Leu-Gln, Trp-Phe-Gln, Trp-Tyr-Leu | 10 to 17 residues |
| CDR-L2 | almost always 16 residues after the end of L1 | generally Ile-Tyr, but also, Val-Tyr, Ile-Lys, Ile-Phe | ? | almost always 7 residues (except NEW (7FAB) which has a deletion in this region) |
| CDR-L3 | almost always 33 residues after end of L2 (except NEW (7FAB) which has the deletion at the end of CDR-L2) | almost always Cys | almost always Phe-Gly-Xaa-Gly | 7 to 11 residues |
| CDR-H1 | approx residue 26 (almost always 4 after
a Cys) [Chothia / AbM defintion]; Kabat definition starts 5 residues later |
almost always Cys-Xaa-Xaa-Xaa | almost always a Trp. Typically Trp-Val, but also, Trp-Ile, Trp-Ala | 10 to 12 residues [AbM definition]; Chothia definition excludes the last 4 residues |
| CDR-H2 | almost always 15 residues after the end of Kabat / AbM definition of CDR-H1 | typically Leu-Glu-Trp- -Ile-Gly, but a number of variations |
Lys/Arg- -Leu/Ile/Val/Phe/ Thr/Ala- -Thr/Ser/Ile/Ala |
Kabat definition 16 to 19 residues; AbM (and recent Chothia) definition ends 7 residues earlier |
| CDR-H3 | almost always 33 residues after end of CDR-H2 (almost always 2 after a Cys) | almost always Cys-Xaa-Xaa (typically Cys-Ala-Arg) | almost always Trp-Gly-Xaa-Gly | 3 to 25(!) residues |
.
 |
ABG
: directory of 3D structures of antibodies Antibodies – structure and sequence by Andrew C.R.Martin BLAST for antibody sequences at NCBI Calculation of Antigen Selection Pressure on Immunoglobulin Genes Canonical structuresand conformations of CDR3 in the VH domain How lymphocytes produce antibody from Cells Alive Immune Recognition Group ImMunoGeneTics (IMGT) : LIGM Database Mats Ohlin Home Page Mike Clark's Immunoglobulin Structure/Function Home Page The Antibody Cross Reactivity Resource The Antibody Resource Page The Antibody Web V Base : the directory of human V gene sequences Web Antibody Modelling (WAM) |
(see also B-cell Ag
receptor pathway [free registration required]) :
. Ag engaging
and cross-linking mIg causes tyrosine kinases to
phyosphorylate Y residues of the ITAMs. 45 / B220 / LCA, which dephosphorylates
tyrosine residues, is also activated in a negative
feedback. envelope
together with CD20 (a
33- to 36-kDa transmembrane phosphoprotein involved in the
activation, proliferation, and differentiation of B
lymphocytes encoded by a gene on 11q12-p13.1, belonging to
the TM4 span tetrafamily together with FceRIB and Htm4; not to be
confounded with the tetraspanin family, which include CD37,
CD53, CD81 and CD82). The predicted amino acid sequence of
the CD20 suggests 4 transmembrane-spanning regions with both
N- and C-termini located in the cytoplasm. It works as
a putative store-operated Ca2+
channel (SOCC) activated by the depletion of intracellular
calcium following BcR ligation. The SOCC could be created by
CD20 multimers, or be a separate protein activated
sterically or via second messengers. CD20 is expressed since
pre-B cells to m+ B
cells to m+d+ B cells to activated B
cell to B blast, while is absent on pre-B and plasma cells.
Expression of CD34 and CD20 are mutually exclusive. CD20
expression is higher in GC B cells than in mantle zone
B-cell than in marginal zone B-cells. CD20 expression can be
upregulated at the transcriptional level by bryostatinref
via ERK and PKC, but not p38 nor dexamethasone, making B
cells more sensitive to apoptosis induced by anti-CD20 monoclonal
antibodies :
this cause relocation into lipid rafts. The lack of sIg
expression in CD20+ B cells is a surrogate of
neoplasia. CD20-/- mice display a normal
phenotype. capable,
once degraded and MHC II co-presented, to be bound from a
host TcR, the B lymphocyte can be primed. When a B lymphocyte acts as a APC, the
epitope MHC II co-presented
to the CD4+
T-cell and recognized by the TcR is not necessarily the same
that is recognized by its own BcR. => E47
/ TCF3 =>2 highly conserved intronic
E-boxes => activation-induced
C
deaminase (AID). According to
different hypotheses AID may act on ...) : deamination of C
results in an activating C=>U transition in
mRNA coding for the involved endonuclease. Because
phosphorylated histone H2AX (g-H2AX,
which
forms next to double-stranded DNA breaks (DSBs))
focus formation at the IgH loci does not depend on
uracil–DNA
glycosylase
(UNG), but CSR is reduced in the absence of
UNG, this indicates that UNG has a role in CSR
downstream of DNA cleavage, which contradicts the
DNA deamination model. In support of this, no
difference in the IgH mutation rate between cells
expressing or not expressing the UNG inhibitor
Ugi; because mutation results from DNA cleavage
during CSR, it seems probable that UNG is not
required for DNA cleavageref.
UNG mutants that lack UNG catalytic activity but
retain DNA-binding activity were shown to recover
wild-type levels of CSR in UNG-deficient B cells.
The importance of UNG for CSR in the absence of
its catalytic activity indicates that it might
have a structural role, functions as a scaffold to
recruit repair proteins to the DNA after DNA
cleavage caused by an AID processed endonuclease.
The role of such an endonuclease is also supported
by showing that de novo protein synthesis
is required for DNA cleavage in CSRref.), resulting in strand breakref.
In addition, AID is expressed in extrafollicular large
proliferating B cells, 14% of which have nuclear AID.
GC and extrafollicular AID+ cells express
E47 but not the inhibiting BHLH protein Id2. Outside
the GC, AID+ B cells are in contact with T
cells and show partial evidence of CD40 + bcr
stimulation-dependent signature (CCL22, JunB, cMYC,
CD30) but lack early and late plasma cell markers. The
distribution of nuclear AID is consistent with the
topography of SHM and CSR inside the GC and in
extrafollicular activated B cellsref.
genes are located in a cluster of pluripotency genes
including Nanog and Stella
and are co-expressed with these genes in oocytes,
embryonic germ cells, and embryonic stem cells. These
results suggest that Aid and perhaps some of its family
members may have roles in epigenetic reprogramming and
cell plasticity. Transition in CpG dinucleotides is the
most frequent mutation in human genetic diseases, and
sequence context analysis of CpG transitions in the APC
tumor suppressor gene suggests that DNA deaminases may
play a significant role in tumor etiologyref.
: it
up-regultes Id2,
which acts as a negative regulator of E2A,
whose activity is required for IgE class switching.
cells, or by
activated mast cells, basophils and eosinophils. IL-2,
IL-5,
IL-6,
and TNF-a
are known to act in concert.
binding by TNFSF8 / CD153 / 30L negatively regulates CSR.
Isotype switching is cell division linked : as human B cell
switching cytokines (such as IL-4,IL-10,
and IL-13) can also promote B cell
proliferation they could not be true switching factors. .
]
and by ~ 50% of all Streptococcus
pyogenes,
but attempts to use these proteins as IgA-purifying
reagents have been hampered by unsuitable binding
properties and/or affinity for human plasma proteins other
than IgA. Anyway the Sap peptide (corresponding to aa
35-83 of protein Sir22 / M22) contains a 29 aa sequence
that is sufficient for specific IgA binding.
, where they confer passive natural
immunity). The mucosal surfaces can be reached by ...
by phagocytes (opsonization;
only when phagocytes are available) and antibody-dependent
cell-mediated cytotoxicity (ADCC) (only when
killer cells are available) through Fc receptors (FcRs)
: high affinity FcRs are referred to as FcRI, and low
affinity FcRs are referred to as FcRII/III. High affnity
FcRs can bind noncomplexed, monomeric Igs, while low
affinity FcR bind aggregated Igs or Abs complexed to
multivalent Ags. Please note IgE is the only isotype
which can bind its receptors even when the antigen is
not bound. The FcR is found also associated to the collagen
receptor glycoprotein VI on platelets. Fc
receptors can be divided into 2 groups based on their
signaling capability and structure. The first and most
common type of Fc receptor is a multichain heterocomplex
composed of a ligand-binding a-chain
and one or more signal-transducing g-chains.
The second type of Fc receptor is a single-chain
transmembrane receptor containing a signal-generating
motif(s) in the cytoplasmic domain and, thus, not
requiring another signal-transducing subunit-, TNF-a-, or GM-CSF-stimulated neutrophilsref1,
ref2; => cell activation,
opsonization) : a-chain
gene expression is up-regulated by YY1,
PU.1
and GATA1,
down-regulated by Elf-1.-containing) on neutrophils,
monocytes and macrophages (=> cell activation
by up-regulation of indoleamine
2,3-dioxygenase
(IDO) and 3-monooxygenase;
opsonization), natural killer cells, platelets,
placental trophoblasts and endothelial cells ;-containing) =>
alternative mRNA splicing =>, placental trophoblasts
and endothelial cells : it lacks a domain
encoded by the first intracytoplasmic exon and
when coaggregated with FceRI, it is
rapidly Tyr-phosphorylated and recruits SHIP-1
=> recruitment of p62dok
and RasGAP1=>
inhibition
of ERK1 and ERK2
=> inhibitory effects on cell activation
(prevention of mast cells activation in
presence of IgGs !).
It internalizes IgG immune complexes for Ag
presentation mainly in phagocytosis.-containing) on human natural
killer cells, neutrophils,
placental trophoblasts and endothelial cells?
and myeloid precursor cells, including
eosinophilsref)
=> cell activation and ADCC; no homolog in Mus
musculus; on neutrophils
and natural killer cells => phagocytosis) molecules. It can form
both non-covalent and covalent dimers in the absence
of its ligand, IgG. The most notable feature of the
interaction of FcRn with IgG is its pH dependancy :
the Fc portion of IgGs binds FcRn with a high
affinity at pH 6.0 and is released at pH 7.2. It is
responsible for IgG transport across the intestinal
epithelium in newborn rodents, is expressed in
epithelial cells in adult humans and non-human
primates. A role for FcRn in IgG homeostasis in
humans has been hypothised, but to date, there is no
direct evidence to invoke its role in such a
process. This suggests, along with colocalization
studies, that for cells bathed in near neutral pH,
the IgG/FcRn complex forms within acidified
endosomes. More precisely, FcRn acts as a salvage
receptor, binding and transporting pinocytosed
IgGs in intact form both within and across cells,
and rescuing them from a default degradative
pathway. Although the molecular mechanisms
responsible for salvaging IgGs are still largely
unknown, it is thought that unbound IgGs are
directed toward proteolysis in lysosomes,
whereas bound IgGs are recycled to the surface
of the cells and released. This control takes place
within the endothelial cells located diffusely
throughout adult tissues. In contrast to mouse FcRn,
human FcRn is surprisingly stringent in its binding
specificity for IgG derived from different species.
Human FcRn binds to human, rabbit and guinea pig
IgG, but not significantly to rat, bovine, sheep or
mouse IgG (with the exception of weak binding to
mouse IgG2b). In contrast, mouse FcRn
binds to all IgG analyzed. The lack of binding of
human FcRn to mouse IgG1 has been
confirmed using transfectants that have been
engineered to express human FcRn on the cell
surface. These results provide a molecular
explanation for the enigmatic observation that mouse
IgG behave anomalously in humansref.
FcRn is expressed within azurophilic and specific
granules of neutrophils, and relocates to
phagolysosomes upon phagocytosis of IgG-opsonized
bacteria. FcRn enhances phagocytosis in a pH
dependent manner which is independent of IgG
recycling. IgG-opsonized bacteria were inefficiently
phagocytosed by neutrophils from b2M knock-out or
FcRn a-chain knock-out
mice, which both lack expression of FcRn. Similarly,
low phagocytic activity was also observed with
mutated IgG (H435A), which is incapable of binding
to FcRn, while retaining normal binding to classical
leukocyte FcgRs. Finally,
a TAT peptide representing intracellular
endocytosis- and transport motifs within FcRn,
strongly inhibited IgG-mediated phagocytosis. These
findings support a novel concept in which FcRn
fulfills a major role in IgG-mediated
phagocytosisref. or
through ITIMref1,
ref2.
Both AIHA and ITP are mediated by FcgRs
found on phagocytes (macrophages) as part of the
reticuloendothelial system (RES) in the spleen and liver
and may lead to thrombocytopenia or anemia, respectivelyref.
Various observations by multiple laboratories have
determined the role of FcgRs
in these diseases most conclusively in murine models
lacking the common g-chain
(KO). Experimentally induced AIHA and ITP are markedly
decreased in mice lacking the g-chainref.
Additionally, administration of mAb 2.4G2, which binds
to and blocks mouse FcgRII
and FcgRIII, allows a rapid
recovery after induction of AIHA or ITP. Similarily,
administration of GM-CSF has been shown by various
groups to accelerate AIHA potentially due to
upregulation of FcgRIref.
These reports show that altering the balance of
stimulatory to inhibitory FcgRs
has a marked effect on disease progression and
susceptibility. As such, viral infection has been shown
to stimulate or increase susceptibility to both AIHA and
ITP. However, the mechanism(s) by which viral infection
does so has yet to be fully elucidated. Potential
scenarios of viral infection that could lead to this
outcome include stimulated production of IFN during
viral infection that causes upregulation of FcgRI. Alternatively, viral
infection may cause a change in the expression pattern
of FcgRs due to
transcriptional activation or other mechanisms.
and with ageing.
,
monocytes/macrophages, interstitial DC, immature
and mature monocyte-derived DCref,
and eosinophils => cell activation, ADCC). The FcaRI-Fca
complex consists of 2 FcaRI
molecules and a single Fca
dimer, with one receptor binding to each of the Ca2-Ca3
junctions. As the pIgR ectodomain of SIgA seems to interact
with residues of IgA that are required for binding
of the FcaRI-binding
site, SIgA requires the presence of an integrin
co-receptor for signalling through FcaRI, and even then, cannot
trigger phagocytosis. Its expression and function
can be up-regulated by fMLP, GM-CSF, IL-8, IL-1b,
TNF-a,
CD11bCD18
/ aMb2 integrin /
Mac1 / CR3 and LPS, and
down-regulated by TGF-b1.
The FcaRI
ligand-binding chain contains a short cytoplasmic
tail and its expression and function are dependent
on FcR
g-chains, which
contain ITAMs.
(expressed on immature monocyte-derived DCref) apical surfaces), basophils, and Langerhans
cells, and inducible on eosinophils (a(FcRgFcgRI, FcgRIIIA, and FceRI)2 trimer on monocytes
and eosinophils from atopic patients) : the a-chain
is the only Fce-binding
subunit, while aand g ones are signal
transducing subunits. The a-chain
can be bound and activated by : of the cytoplasmic region of FceRI b
an g subunits, enabling
the recruitment of further Lyn and Syk,
respectively, through SH2 domain-pY interactions :
newly recruited PTKs are activated by
transphosphorylation of Tyr residues in their
activation loops and by conformational changes in
the case of Syk.
Active Lyn and Syk phosphorylate themselves and other
protein substrates such as PL-Cg1, PL-Cg2, PI(3)K
and Btk.
Lysophospholipids are fusogenic and allow
degranulation within 1'. Genes induced after FceRI stimulation include : CCL-2 / MCP-1, CCL-4 / MIP-1b,
IL-4, IL-5, IL-6, TNF-a, GM-CSF,bA
subunit of inhibin/activin, IL-1ra, and (after 24 hours) kynurenine
3-monooxygenase.
-inducible)
on
B lymphocytes
and eosinophils,
some B and T lymphocytes,
and intestinal epithelial cellsrefref
(more highly phosphorylated in B cells than in the 293
cell lines). B-cell-specific AID–RPA complexes
preferentially bind to ssDNA of small transcription
bubbles at SHM 'hotspots', leading to AID-mediated
deamination and RPA-mediated recruitment of DNA repair
proteinsref.
N-terminus mutations in AID impair SHM but not CSR, while
the C-terminus is not required for SHMref.
Rheumatoid
factor+
B cells undergo SHM at the T-zone-red-pulp border due to
abundance of self-antigen that prolongs the proliferation
of B cells at extrafollicular sites, allowing them to
reach a threshold number of cell divisions for the
initation of mutation (it is not known whether there might
be normal immune responses that follow similar rules).
Mutational activity could result from a specific mechanism
that actively introduces nucleotide changes or an
ineffective repair mechanism that does not correct errors
efficiently or precisely or both. The net result is
hypermutational activity that is highly targeted (>
50%) to RGYW (purine, G, pyrimidine, A/T) motifs
on each DNA strand and provides the observed G:C bias of
mutations. In contrast, the acquisition of mutations also
occurs frequently in nontargeted sequences. There might be
2 separate mechanisms for SHM : the first is
MMR-independent, targets RGYW motifs, and occurs in germinal
center
(GC),
whereas the second is MMR dependent, does not target
specific motifs, and does not require germinal center
formation. Variable but not constant regions of Ig genes
contain a high frequency of DSBs near RGYW hotspots,
suggesting that several error-prone DNA polymerases (h,
i, z
and m) might be involved in
creating mutations during the repair of these DSBs.
Transcription through mammalian switch regions, because of
their GC-rich composition, generates stable R-loops, which
provide ssDNA substrates for AID. However, the Xenopus
laevis switch region S, which is rich in AT and not
prone to form R-loops, can functionally replace a mouse
switch region to mediate CSR in vivo. X.
laevis S–mediated CSR occurred mostly in a region of
AGCT repeats targeted by the AID–replication protein A
complex when transcribed in vitro. AGCT is a
primordial CSR motif that targets AID through a non-R-loop
mechanism involving an AID–replication protein A complexref.
SHM has been difficult to study in vivo because
the DNA in and around rearranged V genes undergoes random
point mutation so that many different mutations occur.
Furthermore, cells expressing mutated Igs are then
subjected to antigen selection, which selects a subset of
the mutated Igs that have increased affinity for the
antigen. Mice transgenic for a reporter transgene (HuG-X)
that encodes a chimeric Ig heavy chain (composed of a )
: so at least bivalent Ags are necessary (e.g. there is no
complement activation with anti-Rh IgG) and Klebsiella
pneumoniae-phosphorylcholine
complexes]
produces CRIT,
a C2 decoy receptor]
, bind to CCP3 of the a-chain of C4BP, which leads to
a decrease in serum killing, allowing a certain
threshold of bacteremia]
as T-DAF] : Daf dissociates C3/C5 convertases
that assemble on host cells and thereby prevents
complement activation on their surfaces. During primary
T cell activation, the absence of Daf on
antigen-presenting cells (APCs) and on T cells enhances
T cell proliferation and augments the induced frequency
of effector cells. The effect is factor D- and, at least
in part, C5-dependent, indicating that local alternative
pathway activation is essential. Cognate T cell–APC
interactions are accompanied by rapid production of
alternative pathway components and down-regulation of
Daf expression. The findings argue that local
alternative pathway activation and surface Daf protein
function respectively as a costimulator and a negative
modulator of T cell immunity and explain previously
reported observations linking complement to T cell
function. The results could have broad therapeutic
implications for disorders in which T cell immunity is
importantref.
by human neutrophils. As a highly active and small
soluble protein that acts exclusively on surfaces,
staphylococcal complement inhibitor may represent a
promising anti-inflammatory moleculeref.]
substitutes for the C3-dependent
C5 convertase. This linkage between the complement and
coagulation pathways may represent a new pathway of complement
activation. Plasma from C3-/- mice contained
threefold higher levels of thrombin activity compared to plasma
from C3+/+ miceref.
Extrahepatic derived C3 forms a large proportion of the
circulating C3 levels (0.1 to 2.6% of the total circulating C3
during the immediate post-HSCT period in response to
inflammatory stimuli and 3.1-5.7% in the liver transplant
group). In the resting state, most of this extrahepatically
derived C3 comes from nonmyeloid sources. In addition,
monocytes, which in the resting state contribute negligible
amounts of C3, have the potential when stimulated to contribute
significantly to the total systemic C3 poolref.
: strong
anaphylotoxin and chemotaxin,
macrophages, FDCs,
RBCs, eosinophils, some
astrocytes, glomerular podocytes : in non primates also on
platelets, where binding causes degranulation). CRIg, a
complement receptor expressed on macrophages, binds to C3b
and iC3b mediating phagocytosis of the particles. Activation
of C3 induces major structural rearrangements, including a
dramatic movement (>80 Å) of the
thioester-bond-containing domain through which C3b attaches
to pathogen surfaces. CRIg is not only a phagocytic
receptor, but also a potent inhibitor of the alternative
pathway convertases. The structure provides insights into
the complex macromolecular structural rearrangements that
occur during complement activation and inhibitionref, eosinophils,
macrophages, FDCs,
platelets, uterus cervix and
nasopharyngeal epithelium, also a receptor for HHV-4 / EBV) (+ factor H as
cofactor) -mediated proteolysis
, eosinophils,
macrophages, FDCs,
platelets, uterus cervix and
nasopharyngeal epithelium), eosinophils,
macrophages, FDCs,
platelets, uterus cervix
and nasopharyngeal epithelium), eosinophils,
macrophages, FDCs,
platelets, uterus cervix
and nasopharyngeal epithelium) : opsonin, macrophages,
FDCs,
RBCs, platelets, eosinophils, some astrocytes,
glomerular podocytes) : opsonin and involved in immune
adherence + factor H as
cofactor proteolysis
: strong
anaphylotoxin and chemotaxin
from
occurring. family of small,
secreted proteins which have the common ability to bind small
hydrophobic ligands. While specific roles have been identified for
C8a and C8b
in the formation and function of the MAC, a function for C8g and the identity of its ligand are
unknown. The binding of C8 increases the
penetration of the complex into the membrane. after 10 minutes at 37°C., JNK,
cPL-A2, and COX-2.
. is
preferred to necrotic death. For killing to be selective the
killer cells needs to be near the targeted cells : proximity can
be achieved through
) at the immunological synapse (the
contact zone between the killer cell and target cell due to
the specific reorganization of cell-surface membrane
proteins). Granules contain ...
mediates an increased protection against the action of
cytolytic proteins released by activated NK cells, possibly by
a membrane-stabilizing mechanisms, rather than by delivering
negative signals to NK cellsref]
protects NK cell from autolysis]
,
thrombin receptor, nucleolin,
IL-1b, pro-urokinase-type
plasminogen
activator (pro-u-PA), the nucleosome assembly
protein PHAPII,
histone H1 family members and lamin A/C.,Fungi
and helminths,
inducing increased permeability and osmotic lysis. CTLs
express granulysin after stimulation by IL-15
and this expression is abrogated after treatment with SrCl2.,
which binds to TNFRs on the surface of the targeted cell. on their surface
with CD95 /
Fas / Apo-1 on
surface of the target cell. Only when the granule pathway is
compromised are significant levels of Fas-mediated killing
observed. Fas is up-regulated by IFN-g secreted by the
killer cell.RO+),
rather than a naive phenotype, which indicates prior
exposure to these self-Ags, even in germ-free
conditions. They reside in tissues rather than in lymph nodes., the Gi-coupled
peripheral endocannabinoid receptor, have profound deficiencies in
splenic marginal zone, peritoneal B1a cells, splenic memory CD4+
T cells, and intestinal NK cells and NKT cells. These findings
partially phenocopy and extend the lymphocyte developmental disorder
associated with the Gai2-/-
genotype, and suggest that the endocannabinoid system is required
for the formation of T and B cell subsets involved in immune
homeostasisref
Copyright © 2001-2014
Daniele Focosi. All
rights reserved | Terms of use | Legal notices
|
|
|
for |
|
