Deutsches Rheuma Forschungszentrum Berlin, Robert
Koch Institute, Haus 11, Nordufer 20, D-l000 Berlin 65
Tel: (030) 454 2060
Fax: (030) 454 2090
This paper tries to put recent work from my laboratory into the
wider context of the use of peptides in T -cell biology. The names
of my old colleagues in London can be found in the references (Villarreal
et al ]990, Robertson et a] 1992), as also can those of my new ones
in Berlin (Robertson et a11992, Brunner et a] 1992), who did the
work. In truth our contribution to this burgeoning field has been
slight, although we have enormously enjoyed playing a small role
in a great enterprise. It is one which is still gathering speed.
Perhaps this account will give some idea of activity which is moving
from laboratory studies into diagnostics, and on from there on into
therapy. The trial of orally administered type II collagen in rheumatoid
arthritis which my colleague Dr. J.S. Sieper and I have been planning
has been a great stimulus to thought. The title here is misleading
in so far as advances in understanding the trimolecular interaction
between MHC molecule, peptide, and T -cell receptor are not covered.
They make up another whole branch of the subject, well reviewed
by Rothbard and Gefter ( 1991 ).
What is an epitope?
An epitope, by definition, is that part of an antigen which is
recognized by a lymphocyte. Luckily this discussion is confined
to T -cells, where the question of what is recognized can be answered
very simply, as has been discovered only quite recently (reviewed
in Rothbard and Gefter 1991). In brief, major histocompatibility
molecules (MHC) of both class I and II type have a groove that accommodates
peptide nonamers (i.e. sequences of nine amino acids), and it is
these nonamers (plus the surrounding MHC structure) that are recognised
by the antigen-specific receptors (TcR's) of T -cells. A nonamer
constitutes the "epitope" or determinant part of an antigen which
is recognised by T -cells. In principle it is possible simply to
scan epitopes in an entire protein by means a set of "nested" (overlapping)
nonamers, but for most proteins this would be prohibitively expensive.
Rules for predicting epitopes have been formulated, but these cannot
yet be relied on. An interesting question is why a length of exactly
nine amino acids has been chosen. The hard nosed biochemist might
argue that this size is dictated by the geometry of the MHC molecule.
These molecules evolved from a single domain ancestor of immunoglobulin
type, and no doubt there are limits to what members even of that
super-family can accomplish. I doubt however whether those limits
are tight enough to specify the length of the groove so precisely,
and prefer a more evolutionary line of thought. It seems likely
that the length reflects a balance of selective pressure between
two opposing needs: on the one hand to conserve as much of the T
-cell repertoire as possible, and on the other to prevent pathogens
from building proteins invisible to the T -cell system. One can
imagine primitive vertebrates trying out various lengths so as to
find out which one suit them best, with the outcome shown in figure
I. Perhaps the balance illustrated there could be tested against
the nonamer outcome by calculation, provided that the number of
amino-acid permutation allowed is known; pockets in the MHC structure
specify restrictions, and so on. That expert modeler of the immune
system Alan Perelson is tackling the problem, which is good news.
Epitope analysis: how epitopes are identified
Hunting for epitopes is easy enough in principle. All that is needed
is (1) a screening agent, normally a population of activated T -cells,
(2) a screening procedure, such as a proliferation assay, and (3)
a set of pep tides derived from the protein under study. As regards
the screening agent, unselected populations of activated T -cells
can of course be obtained from human disease patients or from immunized
animals. Usually these are not suited to the task because of their
low level of reactivity, although in our experience they give workable
signals with exceptionally powerful microbial antigens (VillarrealRamos
et a] 1991). In the mouse this problem can best be solved by making
T-hybridomas, as will be mentioned in connection with our F liver
protein study. Unfortunately this technology has not yet been developed
for human T cells, which leaves a conspicuous gap in human immunology.
Perhaps someone with experience of growing human T -leukaemia cells
may read this paper, and come to the rescue. So instead, one can
try to make use of antigen-specific human T -cell clones. That is
a troublesome business, and introduces an element of selection while
the clones are being picked. Perhaps the best thing is to compromise,
and flit to and fro between mouse and man trying to spot epitopes
which work in both species. This in fact was what was done in the
lead study on HIV epitopes that is discussed below. As regards screening
procedures, proliferation assays no doubt set the standard. Reactions
of T -hybridomas have to be assayed by IL-2 release, and even with
unselected T cells the trend is towards measuring cytokine release
rather than proliferation. IFNy is sometimes preferred to IL-2 for
this purpose, as the assay has less problems with cytokine-consumption
by receptors on activated T -cells. In no human autoimmune disease
have the culprit T -cells been definitively identified. Accordingly
methods are being developed for screening which do not depend on
having specific T -cells. Thus my colleague Angelika Daser is scanning
the 57 kD heat-shock protein of Chlamydia trachomatis for peptides
able to bind to HLA B27, by means of a mutant B cell line provided
by Dr Donald Pious (Seattle) that lacks the so-called "transporter"
genes (alias "pump", "TAP", "ring", or " ABC" A TP-binding casette
genes). These cells express low levels of MHC class I proteins because
peptides are not transported across their endoplasmic reticulum
and so cannot stabilise the nascent proteins. By providing extrinsic
peptides the proteins can be stabilised and will then accumulate
in increased quantity. Because HLA-B27 has been found guilty by
association in several rheumatological diseases, and because Chlamydia
induce B27-associated reactive arthritis, we plan to develop this
screening procedure further. An important step will be to cross-test
the peptides for activity in an in vitro competition assay with
B-27-restricted T-cells specific for a third-party epitope (Guillet
et aI1987). As regards making sets of peptides, mention has been
made of the prohibitive expense of synthesising a complete set of
nonamers in order to scan a protein. It seems better to start either
with cleaved fragments of the protein (e.g. cyanogen bromide cleavage),
or to take advantage of advances in biotechnology to make recombinant
peptides. This has the advantage that one can start with large peptides,
and then move on immediately to their smaller fragments. New England
Biolabs sell an expression system using the E. coli maltose binding
protein which is giving us excellent results. Peptides of 50-100
amino acids are well within its capability, although uniformly high
yeilds are not expected. For experiments with definitive nonamers,
chemical synthesis is faster, easier and cheaper than recombinant
DNA technology. For epitope screening of larger, overlapping protein
fragments however the maltose binding protein system seems to be
extremely efficient. Starting from cDNA, in our case from that of
type II collagen kindly given by Professor Vuorio (Turku), Roland
Lauster, Eva Rajnavölgyi and Sinasi Gayrak have amplified those
parts which encode the desired stretches of amino acids, using the
polymerase chain reaction (PCR). The synthesis of specific 3' and
5' primers allows cloning of the amplified fragments into an E.coli
plasmid vector, so that the collagen peptide is expressed as a fusion
protein C-terminal to the maltose binding protein. In our first
set of experiments the fusion proteins represent 20-40 % of the
total E.coli proteins after chemical induction of gene expression.
Further purification is achieved by the maltose binding capacity
of the fusion product on an affinity column. The two fusion partners
of the protein can subsequently be separated by the use of factor
Xa proteinase. The corresponding recognition sequence has been constructed
as a joining element by the manufacturers of the plasmid.
Epitope selection: why so few?
Most of the T -cell response normally focuses on a small number
of epitopes on anyone protein; the control experiment with lysozyme
in Lehmann et al (1992) provides a good example. Selection operates
at various levels: during proteolytic cleavage within antigenpresenting
cells, by MHC molecules, and within the T -cell repertoire as a
result of negative selection. Perhaps competition between peptides
for binding to MHC molecules is the point at which selection operates
most stringently: "epitope dominance" is a term applied to the outcome
of this competition. As is further discussed below, the dominant
epitope does not entirely monopolise the response. There is scope
for other epitopes to join in, and these additional epitopes can
be exploited for diagnostic purposes as described below.
Using epitopes to explore the T -cell repertoire: the cut-off
Single, intact proteins are widely used for exploring the T cell
repertoire. Indeed exploring reactivity to such selfproteins as
myelin basic protein, acetyl choline receptor, microsomal thyroid
peroxidase and type II collagen has become something of a world-wide
industry, as all of them are implicated one way or another in autoimmune
disease. The problem is that although reactivity towards these proteins
may rise in the course of disease, T -cells from normal individuals
can also react, although usually to a lesser extent. Furthermore
not all patients show heightened reactivity. One can argue to and
fro. For instance, the level of reactivity found in healthy individuals
can be dismissed as ineffective, and ascribed to activation by cross-reactive
foreign antigens. In trying to sort matters out one runs into a
technical difficulty that is inherent in any proliferation assay
conducted with a single-protein antigen: there is a range of normal
variation, which means that a cut-off has to be set at a moderately
high level, so that weak positive responses tend to score as negative
The problem of the single-protein assay has been attacked in a promising
way in the field of Human Immunodeficiency Virus research. An important
question is whether individuals are ever able to resist HIV infection.
Accordingly, Berzowsky, Shearer and their colleagues constructed
a set of six peptides from the viral envelope that could be recognized
by T -cells from immunized mice and from HIV-infected human, of
diverse MHC type (Berzowsky et al 1991). Reactivity towards these
peptides was then examined in seronegative but high risk groups,
such as homosexual men with recent exposure to HIV from their partners
(Clerici et al 1992). This enabled a small but highly significant
sub-group to be identified, who did react to the peptides but remained
seronegative, suggesting that transient infection had indeed been
resisted successfully. The reaction to the peptides was convincing
precisely because individuals who reacted at all did so to several
of the peptides. It is unlikely that such a firm conclusion could
ever have been reached with a single-protein assay. This study also
disposes of the reservation concerning peptide stimulation that
it might not be possible to find peptides able to bind to the range
of HLA molecules that occur in the human population. It is true
that this study was carried out with peptides derived from a viral
rather than an autoantigen. This in fact strengthens the argument,
as viral peptides unlike autoantigens have no doubt been selected
in evolution to avoid binding to HLA molecules. A third significant
point that emerges from this study is that an excellent way of assessing
the reactivity of T -cells from peripheral blood is by IL-2 release.
This assay was tested extensively in parallel with a conventional
proliferation (tritiated thymidine incorporation) assay (Clerici
et al 199l), and has now become standard practice in that group.
Activated and quiescent T -cells
When self-proteins are used to explore the T cell repertoire, as
mentioned above, just what is being explored? Is only the repertoire
of activated T -cells detected, or is it the entire repertoire?
This important question has been largely answered by recent analysis
of the T -cell subsets marked by different CD45R isoforms (reviewed
in Brunner et al1992). It seems that expression of CD45RO marks
an activated T -cell population, which gradually reverts to CD45RA
expression and quiescence (this view is not universally accepted;
Brunner et al draw attention to one crucial gap in the available
information). Only .CD45RO T -cells can respond in a proliferation
assay as It IS normally carried out, i.e. without costimulation.
With costimulation, e.g. from a lectin, quiescent, CD45RA cells
can also participate (Sanders et al 1989). According to this view
there are two repertoires, one of which has almost entirely escaped
attention: by Introducing costimulation the world-wide industry
could double its output, and would then have more to tell us about
the underlying nature of autoimmunity.
What do we expect to find ?
My colleague Susanne Schneider has discovered that immunization
of mice with allo-F-liver-protein (immunogenic in vivo) raises a
population of CD4 -cells identified via T -hybridomas as able to
respond in vitro to self-F-liver-protein (although this protein
appears to be completely non-.immunogenic in vivo). These may simply
be THl cells, in contrast to TH2 cells which appear inactive in
vivo,.a possibility that she is trying to test by manIpulatIons
wIth IL-4. A more interesting possibility is that she may have come
across an example of positive selection of the T -cell repertoire,
of the type proposed by Cohen and Young (Cohen and Young 1991).
Their immunological "homunculus" is a repertoire that is greatly
expanded in certain areas, particularly by the potential autolmmunIty-inducers
such as myelin basic protein and the others mentioned above. But
they may not be the only inducers of positive selection, and in
F liver protein we may have a different kind of positive selector.
This possibility is supported by the old finding that this protein
IS exceptionally Immunogenic. When mice are immunised with homogenates
of one another's liver in Freund's adjuvant, F liver protein is
the only allotype which generates precipitating levels of antibody.
Generalising, the T -cell repertoire can be considered as having.
a complex structure, with many centres of positive selection (contained,
no doubt, by suppressive mechanisms) and also many holes created
by negative selection. If one were to make a voyage of exploration
starting from an epitope related to self, one would not know what
to expect. The repertoire might be "trimmed" by self, to use Janet
Maryanski's phrase, but equally it might be much expanded.
Epitope spreading: a hallmark of autoimmunitv?
Thus far this discussion has concentrated on crosssectional analysis
of the T -cell repertoire, i.e. what can be found if individuals
are compared at anyone time, as in a case/control study. This sort
of information can be enriched by horizontal analysis, in which
changes in the repertoire of activated T -cells are studied over
a period of time. As mentioned above, the T -cell response is highly
restricted, so that to begin with only a few dominant epitopes are
likely to be recognised. Powerful mechanisms then come into operation
for "spreading" the response from one epitope to another through
cell-cell interactions, both T -Band T -T, and both to and from
CD4-cells (Mitchison 1990b). Lehmann et al (1992) propos.e that
autoantigens may be particularly adept at spreading the response
to "cryptic" epitopes, and that this may. constitute a key mechanism
in generating autoimmune disease. This is a stimulating idea, although
the evidence derived from their single EAE experiment in the mouse
is a little thin. Once again Human Immunodeficiency Virus research
points the way. Two groups have used peptide analysis to identify
epitope dominance in the human cytotoxic T -cell response to the
virus, and both have observed that the dominant epitope change over
a period of months (Nixon et al 1.99 l ' Johnson et al 1992, plus
personal Communications from both senior authors). There is some
ambiguity in these data because of virus selection and the possibility
of reinfection, but on the whole they suggest that epitope shifts
occur fairly commonly during chronic Immunization.
Using epitopes to studv T -cell function
As well as answering repertoire questions, analysis of the T -cell
response can proceed to functional studies on what these cells do
after activation. In man the possibilities are limited, and attention
has focussed on the pattern of cytokine secretion. Hitherto the
main subdivision has been into THO, THl and TH2 cells, in man mainly
identified by secretion of IFNy versus IL-4. This classification,
introduced originally in the mouse, applies on the whole well in
man (Brunner et al 1992). However a fourth important category is
now becoming evident, namely TGFß-secreting (transforming growth
factor ß) T -cells originating in the mucosal tissues (Miller et
al 1992) which is further discussed below. , Cytokine production
patterns can of course be determined in the supernatants of stimulated
T -cells, but a procedure applicable to single cells might be preferred,
and would certainly provide additional information. An attractive
technique involves paraformaldehyde-saponin fixation and cell-opening,
followed by immunofluorescence analysis (Hallden et al 1989, Sander
et al 1991). When used in conjunction with FACS analysis of surface
activation markers, this technique offers the possibility of enumerating
activated T -cells making particular cytokines. This technology
has not yet entered general use, and still needs to be explored
carefully. Many other functional assays are possible in animal experiments.
These include ( 1) IL-2 secretion by T hybridomas, (2) helper activity
for B-cells (Lightstone et aI1992), (3) desequestrating activity
(Dietrich et aI1992), and (4) co-induction of autoimmune disease
such as collagen-induced arthritis (T -cells used in conjunction
with B-cells or anti-collagen antibodies). None of these procedures
have progressed to the point where they need discussion here.
Epitope therapy (1) vaccines
Single-epitope vaccines are attracting enormous interest because
of their apparent simplicity and ease of manufacture by biotechnology
methods. For example, the Walter Reed Army Institute for Medical
Research still hopes to implement a malarial sporozoite vaccine,
in an improved form in which a T-epitope would be combined with
a B-epitope which on its own has given disappointing results. Vaccines
of this sort are open to an objection which Barrie Bloom points
out: they invite the parasite to escape by varying its target epitope.
The Human Reproduction Programme of the World Health Organisation
has long supported development of a single B-epitope vaccine for
use in the only context where this problem does not apply, namely
anti-selfvaccination. The epitope is located at the C-terminus of
chorionic gonadotrophin, a hormone responsible for sustaining pregnancy,
where it is hoped that antibodies could have a contraceptive effect.
But even under these favorable circumstances it is by no means clear
that the singleepitope vaccine will work as well as one based on
the intact protein (Mitchison 1990a).
Epitope theraphy (2)mechanisms of shut-down: blockin clonal elimination.
anergy. bystander suppression.
Negative regulation of the immune response, for the purpose of
intervention in autoimmunity and allergy, offers a greater hope
of success. Peptides have repeatedly been shown to down-regulate
the response in a highly specific manner, but there is much less
agreement on just how they do so. The simplest possibility is that
the peptide pre-empts the MHC molecule which would otherwise drive
the response. This would be beneficial in autoimmune disease, if
the blocked molecule would otherwise present a disease-inducing
peptide to T -cells. Competitive blocking of this sort has been
demonstrated in vitra (Guillet et al 1987), and systematic efforts
have been initiated to implement this possibility in viva (Adorini
et al 1988, Mc Devitt et al 1989). The great attractions of this
approach are that most autoimmune diseases are driven only by a
very limited number of MHC molecules (e.g. rheumatoid arthritis
in northern Europe mainly by HLA DR4), so that the target for blocking
is quite narrow; furthermore the target is a well defined molecule,
whereas the target of approaches directed at T -cells themselves
is undefined, at least in the human autoimmune diseases. The problem
inherent in this approach is that blocking would be hard to maintain,
as both the pep tides and their MHC targets have short half-lives.
Accordingly interest is shifting towards longer-term effects, where
Gefter's laboratory has been remarkably successful in obtaining
long-term suppression of the immune response by subcutaneous injection
of small quantities of T -epitope pep tides (Scherer et al 1989
and pers. comm.). A related study has been carried out on the prevention
of collagen induced arthritis by peptide treatment; after much work
this has culminated in the identification of a single active peptide
(Myers et al 1992) .The question now is how these long-term effects
work. A single petide that can suppress the presumably muti-epitope
response to foreign collagen smells of bystander suppression, a
mechanism discussed below. Gefter himself assigns peptide-mediated
unresponsiveness to the category of "anergy", without worrying too
much about the details of mechanism. Reading the papers of Gefter,
or other recent publications on anergy (Ramsdell and Fowlkes 1992,
Kang et al 1992, Mamalaki et al 1992) makes it all sound so simple.
Negative selection (clonal elimination by apoptosis of reactive
T cells) is what goes on in the thymus; unresponsiveness (other
than blocking) induced in the periphery is mediated by anergy, a
well-defined molecular lesion which is induced whenever the TcR
is engaged in the absence of an appropriate costimulus. The lesion
in the T -cells heals over a period of three weeks, unless renewed
by further costimulus-free induction with the peptide or antigen.
It is doubtful whether anergy is quite that ubiquitous. Indeed that
understates the present position; I know of no evidence that normal
(as distinct from super- ) antigens can induce anergy in viva under
anything approaching physiological conditions. In our experience
tolerance of soluble proteins has much the same properties, whether
induced in the thymus or in the periphery (Robertson et al 1992),
and there is little evidence that the affected T -cells can ever
recover. On the contrary, this form of tolerance behaves as though
mediated by clonal elimination. These doubts were confirmed by the
account given by Philippa Marrack at the 1992 International Congress
of Immunology, of unequivocal clonal elimination brought about by
intravenous injection of superantigens; furthermore the doses required
in her experience seemed very similar to those required to obtain
tolerance of soluble proteins, whether in the thymus or in the periphery.
So where does that leave the Gefter phenomenon? Only time and further
experimentation can tell, but in the meanwhile one needs to keep
an open mind. The issue is not trivial, because although induction
of anergy and induction of peripheral clonal deletion may share
features in common, notably the need to avoid costimulation, they
would presumably have quite different stabilities. In passing, that
fascinating T -cell marker CD28 deserves a mention. This membrane
glycoprotein is a strong canditate for providing the hitherto mysterious
costimulation, via ligation of B7, that is needed to prevent induction
of anergy (Linsley et al 1991 ). One might have hoped that whatever
molecule filled this role would also have explained the inability
of T -cells in the thymus to make positive responses, in contrast
to peripheral T -cells; alas, CD28 cannot do so, as it is well expressed
by thymic T cells (Gross et al1992). The crucial molecular difference
between thymic and peripheral T -cells that makes the former insensitive
to costimulation must lie elsewhere. There remains a fourth possible
mechanism, bystander suppression. The four regulatory subpopulations
mentioned above, THO, THl, TH2 and mucosal T, each secrete at least
one cytokine that can suppress the activity of other T -cells, from
the range of IFNy, IL-4, IL-lO and TGFß (my colleagues A.K.Simon
and J.S.Sieper find that IL-lO is not restricted to TH2 cells as
has been thought, but is produced also by THl clones in man). The
three-cell clusters that mediate T -T help (Mitchison 1990b) would
provide the right kind of structure for these suppressive interactions
to take place in, although that is only a speculation. Some sort
of cytokine-mediated bystander suppression is frequently invoked
as the mode of action of immune suppression genes (Mitchison 1991
), but so far without much hard evidence. The best evidence so far
of bystander suppression comes from the recent work on oral tolerance
that is outlined below.
Epitope therapy (3) routes: through the skin. into the mouth.
or up the nose?
Oral tolerance is an old story with a new logic. As recently as
two years ago, I was writing "some routes of administration proved
more effective than others (for producing tolerance), for reasons
that have never been entirely clear. For instance, oral administration
is particularly effective, possibly because the liver can filter
off particles before they reach lymphoid tissue." (Mitchison 1992).
The portal filtration hypothesis traces back to the 1960's (Howard
and Mitchison 1975), but has never found much experimental support.
The new logic stems from two experimental findings, both concerning
TGFß. One of these is that suppressor T cells generated by oral
tolerization to myelin basic protein suppress in vitro and in vivo
immune responses by the release of TGFß after antigen-specific triggering.
Suppressor CD8 T cells from animals orally tolerized to myelin basic
protein produce a suppressor factor upon stimulation with MBP in
vitro that is specifically inhibited by anti- TGFß neutralising
antibodies (Miller et al1992). In addition, active TGFß1 can be
demonstrated in supernatants of these cells after stimulation. Originally
described as a factor that causes anchorage-independent growth of
fibroblasts, TGFß is a pleiotropic cytokine which mediates tissue
repair (referred to by Mosmann .as an agent responsible for clearing
up after the party IS over ). Of particular relevance is its ability
to inhibit proliferation and differentiation of T cells (Wahl et
al1988; Kehrl et al1987). The second important finding is that TGFß
acts as an isotype-specific switch factor for IgA. Following the
initial report that TGFß specifically enhances IgA production by
lipopolysaccharide-stimulated murine B lymphocytes (Coffman et al1989),
a rash of confirmatory reports have appeared, some of which go into
consIderable molecular detail concerning the mode of action of TGFß
in the switch (e.g. lwasato et al1992). Taken together, these findings
suggest that TGFß secreting T cells have the normal function of
promoting local IgA production in the gut, where this class of immunoglobulin
is mainly needed. They also exert an inhibitory effect on other
T cells, and it is through this latter effect that oral tolerance
operates. When activated through oral intake of an organ-specific
antigen, presumably via uptake by M-cells into Peyer's patches,
they migrate and localise preferentially in the organ, and can there
exert a trigger-specific but effector-non-specific inhibitory effect
on other T cells mediating auto-immune processes, as illustrated
in figure 2. It is tempting to speculate on the possible importance
of local tolerance induction in the gut in connection with the handling
of dietary antigens, but that would take us far into realms of speculation.
In the long run it is likely that attention will shift from oral
administration of protein antigens to nasal administration of peptides.
The gut is not the only site of secretion of IgA .across an epithelium.
The lungs too are rich in IgAsecreting cells, and the airway offer
a tempting alternative route for immune intervention, because of
the relative simplicity of its pharmacokinetics. Peptides offer
flexibility in the choice of epitope and greater scope for chemical
manipulation than do intact proteins. David Wraith (Cambridge University,
personal communication) is obtaining encouraging results in the
suppression of EAE by nasally administered peptides. The question
is entirely open whether Wraith's nasal route will turn out to be
more effective than Gefter's subcutaneous one. Either way, negative
regulation by peptides looks very promising indeed.
T -cell epitopes are now well understood as amino-acid nonamers
binding to major histocompatibility complex molecules. Powerful
methods have been developed for their identification through screening
of recombinant and synthetic peptides. Multiple epitopes from a
single protein are valuable for detecting T -cell reactivity in
disease, currently in human immunodeficiency virus infection, and
in the future in autoimmune disease. Surprises are likely to be
encountered while exploring the T -cell repertoire in this way,
such as positive as well as negative selection of self-reactivity.
T-epitopes are likely to find important applications in therapy,
particularly in down-regulation of the immune response. Multiple
mechanisms of downregulation appear to operate, among which bystander
suppression by TGFß-producing T -cells from the gut is of great
Evolutionary pressures on groove size in the MHC molecule
The presumed mechanism of oral tolerance. An organ-specific
antigen, such as type II collagen, is taken up from the gut lumen
by M-cells and passes into a Peyerrs patch, where it activates
mucosal T cells specialised in TGFß production. These migrate
through lymph ducts and blood into other parts of the body. When
localised in an inflamed joint they are specifically stimulated
by locally released type II collagen to secrete TGFß, which then
non-specifically inhibits the growth and differentiation of the
inflammation-inducing bystander T cells.
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