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Department of Laboratory Medicine and Pathology, University of Minnesota Center for Immunology, Minneapolis, MN 55455
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Accumulating evidence indicates that cytokines play a critical role in driving homeostatic expansion. We have shown that there is a critical role for IL-7 in CD8+ T cell homeostatic expansion and survival (12), in keeping with the pivotal role of this cytokine at multiple stages of T cell life (13, 14). In contrast, IL-2, which dominates regulation of Ag-driven T cell responses, has been reported not to be required for homeostatic expansion (6), although the impact of exogenous IL-2 on homeostatic expansion has yet to be reported. Thus, the role of cytokines in homeostatic expansion vs Ag-driven activation are notably different.
Here we study the impact of supplementary cytokines on CD8 T cell homeostatic expansion. Two cytokines with well-documented effects on CD8 T cell proliferation and differentiation were tested: IL-2 and IL-12. Although IL-2 is a prototypic T cell growth factor, the proinflammatory cytokine IL-12 is implicated in augmenting both CD8 T cell growth and differentiation (15, 16, 17, 18, 19). Indeed, recent evidence indicates IL-12 can provide a critical third signal, along with Ag and IL-2, to activate naive CD8 T cells in vitro (18) and has an adjuvant-like effect in activating CD8 T cell responses to peptide Ag in vivo (19). We report here that IL-12, but not IL-2, enhances homeostatic expansion, leading to amplification of functional T cells. The response to IL-12 is evidently T cell autonomous, because it has its effects even when IL-12R expression is exclusively on the T cells. These data argue that cells undergoing homeostatic expansion are receptive to the proinflammatory cytokine IL-12, and that this factor can modify the size, phenotype, and reactivity of the homeostatically expanded pool.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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OT-I TCR transgenic mice and OT-I.PL mice (expressing the Thy1.1
allele) have been described previously (4, 20). Mice
deficient in IL-12 p40 subunit (IL-12o/o), IL-12R
1 subunit (IL-12Rco/o), and
recombinase-activating gene-1 (RAG-1o/o) were
obtained from The Jackson Laboratory (Bar Harbor, ME) and were
maintained in specific pathogen-free conditions throughout the
experiments. Some mice were subjected to sublethal irradiation (700
rad) 1–2 days before T cell transfer. Some mice were thymectomized,
allowed to recover (for at least 2 wk), and then sublethally irradiated
at least 2 wk before adoptive transfer.
All thymectomized and irradiated mice were maintained on antibiotic water (polymixin B sulfate and neomycin sulfate) and under specific pathogen-free conditions throughout the course of the experiment.
Cytokines
Recombinant mouse IL-12 was obtained from Genetics Institute (Cambridge, MA), and recombinant mouse IL-2 was obtained from R&D Systems (Minneapolis, MN). Cytokines were injected i.p. on days 1, 2, and 3 post-T cell transfer with IL-12 (1 µg, equivalent to 2700 ± 1200 U) and IL-2 (2000 IU/injection), as used previously (19, 21). Cytokines were injected in 100 µl of PBS with 1% mouse serum, and this vector was also used as the control.
Adoptive transfer
Single-cell suspensions were prepared from lymph nodes of donor mice and CD8+ T cells (from OT-I or OT-I-Thy1.1 donor animals) or total T cells (from normal C57BL/6 donors). T cell purification (by negative selection) involved Cellect columns (Cytovax Biotechnologies, Edmonton, Canada) or magnetic cell sorting using MACS microbeads (Miltenyi Biotec, Auburn, CA). For OT-I, the purification was through elimination of CD4 T cells and B cells. For normal B6 donors, only B cells were eliminated. The purity of the T cells ranged from 85 to 95% pure (established by flow cytometric analysis). In some cases naive (CD44low) OT-I CD8 cells were purified. OT-I lymph node cells were depleted of adherent cells (90-min incubation on tissue culture-treated flasks at 37°C) and labeled with FITC-coupled anti-B220, CD4, and CD44 (all obtained from PharMingen, San Diego, CA) Abs (0.125 µg of anti-B220 and CD4/1 x 106 cells, 0.04 µg of anti-CD44/1 x 106 cells). Anti-FITC microbeads (Miltenyi Biotec) were used to negatively select CD44low, CD8 cells with the MACS system. Cells were >95% pure (established by flow cytometric analysis).
Cells were labeled before or after purification with CFSE (Molecular Probes, Eugene, OR) essentially as previously described (4, 22). Briefly, pooled lymph node cells were suspended at a concentration of 1–5 x 107/ml in HBSS. After warming to 37°C, CFSE was added at a concentration of 0.5–5 µM for 10 min with occasional mixing, followed by addition of ice-cold RPMI medium containing 10% serum and cell recovery by centrifugation. Purified donor cells were suspended in PBS and injected i.v. into the tail vein of recipient mice. During multiple experiments 1–3 million cells were injected into irradiated recipients, and 1–5 million were injected into unirradiated recipients. Similar results were obtained regardless of the transferred cell number.
In some cases mice were immunized with OVA peptide (OVAp),4 with or without injection of IL-12 treatment. OVAp was given as two injections (25 µg of peptide/injection) administered s.c. on the lower and upper back on day 14 only. IL-12 (1 µg/injection) and PBS were given i.p. on days 14, 15, and 16, and the mice were harvested on day 17.
Flow cytometry
Recipient mice were sacrificed at the time points indicated, and single-cell suspensions were prepared separately from spleen and a pool of major lymph nodes. Lymph node and spleen cells were then stained with combinations of the following Abs: anti-CD8 conjugated to PE or allophycocyanin, anti-Thy1.1-bio, anti-CD44-PE, anti-CD4-allophycocyanin, or anti-Thy1.1-PerCP and followed with either streptavidin-TriColor or streptavidin-PerCP (all obtained from PharMingen). The cells were analyzed with a Becton Dickinson FACSCalibur (Mountain View, CA) using both CellQuest (Becton Dickinson) and FLOWJO (TreeStar, San Carlos, CA) software.
CTL killing assay
The cytolytic potential of cells was tested in a 51Cr release assay, essentially as previously described (23). Briefly, EL4 tumor cells were labeled with [51Cr]sodium chromate with or without the addition of 10 µM OVAp. OT-I.PL cells were recovered from lymph nodes of adoptively transferred (Thy 1.2) hosts by positive selection over magnetic columns after staining the cells with anti-Thy1.1 Abs (2.5 µg of HIS51-bio Ab/1 x 107 cells) and streptavidin-conjugated microbeads (Miltenyi Biotech). Target cells were washed and incubated with titrated numbers of effector cells in a 4-h assay. Percentages of OT-I cells in the effector population were calculated from flow cytometric analysis of a sample of the lymph node preparation, and the data are presented as adjusted E:T cell ratios to reflect this calculation. Lysis on EL4 cells without OVAp was <5%
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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OT-I transgenic CD8 T cells were adoptively transferred into irradiated wild-type B6 recipients. The recipients received injections of PBS, IL-2, IL-12, or a combination of IL-2 plus IL-12, and the impact on OT-I homeostatic expansion was monitored by CFSE dye dilution and by the total cell numbers of the transferred cells.
Exogenous IL-12 greatly enhanced OT-I proliferation, as measured by
CFSE dilution (Fig. 1
A) and by
total number of OT-I T cells recovered from lymph node (Fig. 1B). In contrast, we observed no effect on OT-I homeostatic
expansion of supplementary IL-2 alone (Fig. 1). However, supplementary
IL-2 did change the response to IL-12; coinjection of IL-12 plus IL-2
resulted in less accumulation of OT-I cells than IL-12 administration
alone (Fig. 1B) and a slight reduction of proliferation
(Fig. 1A). The basis by which IL-12 might alter sensitivity
to IL-2 is addressed later.
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1-deficient (24) hosts. In the
latter recipients, host T and NK cells are unable to respond to IL-12
(24), and thus only the donor OT-I cells would be able to
respond to its presence. As shown in Fig. 2, IL-12 augmented the proliferation of
OT-I cells in both host strains (Fig. 2), arguing that the OT-I CD8 T
cells themselves are receptive to IL-12 signals during homeostatic
expansion. This complements previous data, indicating that IL-12 can
support CD8+ T cell responses to antigenic
stimulation (18, 19), and suggests that IL-12 has a
similar effect on homeostatic expansion.
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A).
This approach efficiently purifies phenotypically and functionally
naive CD8 T cells (1, 18, 19). Once again, we found that
IL-12 augmented the homeostatic expansion of these OT-I cells (Fig. 3B), arguing that the effect of IL-12 is mediated on cells
that were naive phenotype at transfer.
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Previous reports have indicated that in order for T cells to
respond to IL-12 they must have also received a signal through their
TCR (15, 25, 26, 27). In contrast, there is evidence from some
groups that homeostatic expansion can occur in the absence of a
peptide/MHC ligand for the TCR (11). To test whether the
IL-12 effect we observed was dependent on a TCR signal derived from
interactions with self-peptide/MHC complexes, we tested the impact of
IL-12 on OT-I proliferation after transfer into irradiated B6 or
TAP-1o/o recipients. In the OT-I system, the lack
of class I MHC expression due to the TAP-1 mutation severely limits
homeostatic expansion (2, 4). As expected, IL-12 enhanced
proliferation in the B6 hosts (Fig. 4A). Strikingly, IL-12 failed
to increase proliferation in the TAP-1o/o hosts
environment lacking self-peptide/MHC (Fig. 4A). Indeed, if
anything the low grade proliferation we observed in TAP-1 hosts was
slightly reduced in the presence of supplementary IL-12. These
observations are also directly reflected in the total number of OT-I
cells found in the recipients (Fig. 4B). Thus, it appears
that T cell sensitivity to IL-12 during homeostatic proliferation first
requires a signal through the TCR.
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Numerous groups have reported that homeostatic expansion involves not only the proliferation of naive T cells, but also their differentiation into memory phenotype cells (1, 2, 3, 4, 5, 6, 7). In contrast to Ag reactivity, this transition appears not to involve a typical effector cell stage, as judged by the classic up-regulation of activation markers (such as CD69 and CD25), and at least for CD8 cells, their functional activity is more similar to that of memory cells than to that of effector cells (1, 2, 3, 4, 5, 6, 7). Because IL-12 can greatly enhance effector differentiation of CD8 T cells in response to Ag (15, 16, 18, 19), we sought to determine whether IL-12 changed the functional or phenotypic characteristics of OT-I cells undergoing homeostatic expansion.
OT-I cells were adoptively transferred into thymectomized/irradiated B6
recipients (mice were thymectomized to avoid host reconstitution of the
T cell compartment after irradiation). Two weeks post-transfer the mice
were challenged with PBS alone, IL-12 alone, OVAp alone, or a
combination of OVAp and IL-12. At this time point virtually all the
transferred cells had undergone at least one round of division (data
not shown). Homeostatically expanded cells proliferated efficiently in
response to both free OVAp alone and OVAp/IL-12 (Fig. 5), suggesting that they are not anergic.
There was a greater increase in total cell number of OT-I lymphocytes
stimulated with OVAp/IL-12 as opposed to OVAp alone (Fig. 5), in
keeping with data showing that IL-12 can act as an efficient adjuvant
for CD8+ T cell activation (19).
Hence we can conclude that OT-I cells that have undergone homeostatic
proliferation not only can respond to Ag (OVAp), but this response can
also be further augmented by inflammatory cytokines (IL-12). Note that
at this early time point (3 days) after initiating IL-12
administration, there is no effect on OT-I expansion in the absence of
Ag. However, similar experiments in which mice were analyzed 7 days
after starting IL-12 injections showed that proliferation of OT-I cells
is still enhanced by IL-12 (data not shown), implying that reactivity
to IL-12 is maintained throughout homeostatic expansion. We also tested
the functionality of OT-I cells undergoing homeostatic expansion by
performing an ex vivo cytolytic assay. OT-I cells that had undergone
homeostatic expansion in irradiated hosts were poor effector cells
(Fig. 6), as demonstrated previously
(2, 4). Supplementary IL-12 alone did not improve
cytolytic effector function (Fig. 6). However, in vivo antigenic
stimulation of the OT-I cells generated potent cytolytic effectors, and
this was further enhanced by IL-12 (Fig. 6). These data suggest that
OT-I cells undergoing homeostatic expansion are not efficient killer
cells, but can differentiate into effector cells in response to true
antigenic challenge.
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, we found that IL-12 enhances the
expression of CD44 even further, with CD44 expression correlating with
multiple rounds of division. In contrast, CD69 remains low during
homeostatic expansion regardless of the presence of IL-12. CD25 (IL-2R
-chain) is also low on OT-I cells undergoing homeostatic expansion
in the absence of IL-12, but, interestingly, CD25 is up-regulated in
the presence of IL-12 (Fig. 7). CD25 expression was modest, however,
and increased only after around seven or eight cell divisions. In
contrast, CD25 was rapidly up-regulated to high levels in the OT-I
response to OVAp (data not shown), consistent with the reports of
others (5).
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Because IL-12 is induced only during inflammatory responses rather
than constitutively, it seemed unlikely that IL-12 would play a central
role in normal T cell homeostatic expansion. In contrast, we and many
other groups make extensive use of sublethal irradiation as a means of
generating lymphopenic hosts, and it is known that irradiation can
induce the production of a variety of inflammatory mediators
(28). Therefore, we tested the requirement for endogenous
IL-12 in driving homeostatic expansion in irradiated hosts. OT-I cells
were tested for their ability to proliferate in irradiated wild-type vs
IL-12o/o hosts. As shown in Fig. 8, OT-I cells proliferated less (by two
or three rounds of division) in the IL-12-deficient recipients compared
with the control recipients, although there was still clearly a robust
proliferative response. IL-23, a cytokine that shares certain functions
with IL-12, was recently reported (29). Because this
cytokine assembles with the p40 subunit of IL-12 (the chain ablated in
the IL-12o/o animals used here), we cannot
currently determine whether this mild reduction in homeostatic
expansion in the IL-12 p40o/o hosts is due to a
loss of IL-12 or IL-23. In any case, these data suggest that IL-12
and/or IL-23 may play an important, but not essential, role in driving
homeostatic expansion.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TCR engagement is important for homeostatic expansion, but this appears to be an interaction with self rather than foreign or environmental peptide/MHC Ags (1, 2, 4, 6, 8). Furthermore, preliminary data suggested that homeostatic expansion does not follow the same rules as typical antigenic stimulation. For example, T cells undergoing homeostatic expansion do not up-regulate normal early activation markers (including CD69 and CD25), and the response does not appear to require the classic costimulator molecule CD28 (1, 6) (M. Prlic and S. C. Jameson, unpublished observations).
To determine what role cytokines play in driving homeostatic expansion,
we studied the impact of supplementary IL-2 and IL-12 on this process.
IL-2 is known to have multiple effects on T cell expansion and
survival; in some cases it may augment the T cell proliferative
response and in other cases may blunt it (30, 31). In our
experiments we observed no impact of IL-2 alone; this is in keeping
with other reports that homeostatic expansion occurs normally using
IL-2-deficient T cells (6). Furthermore, these data may be
explained by the lack of up-regulation of CD25, the IL-2R -chain,
during homeostatic expansion (2, 5, 6, 7, 32).
Recent evidence has shown that naive CD8 T cells do not differentiate fully when stimulated with Ag plus IL-2/costimulation, but that they also require a third signal that can be provided by adjuvants or IL-12 (18, 19). Thus, in vivo administration of peptide alone can tolerize Ag-specific CD8 T cells (18), while coadministration of peptide and IL-12 supports clonal expansion, differentiation, and development of a memory population (19). We found that IL-12 also augmented CD8 homeostatic expansion, as reflected both by more rounds of proliferation and by increased numbers of donor T cells in secondary lymphoid organs. Previous reports have indicated that for T cells to respond to IL-12 they must have also received a signal through their TCR (15, 25, 26, 27). This also appears to be true in the case of homeostatic expansion, because we saw no effect of IL-12 on OT-I proliferation of survival in (class I-deficient) TAP-1o/o hosts. Thus, we reach the intriguing conclusion that homeostatic expansion appears to be maximal upon signal 1 (TCR ligation, in this case by self peptide/MHC) and signal 3 (in the form of IL-12), but does not require conventional signal 2, as evidenced by the lack of a requirement for IL-2 or classic costimulator molecules (1, 6) (M. Prlic and S. C. Jameson, manuscript in preparation).
Taken together our data indicate that homeostatic expansion involves an
atypical pattern of cytokine reactivity, in that T cells develop
reactivity to one inflammatory cytokine (IL-12) but not another (IL-2).
In contrast, reactivity to both these cytokines is typical of CD8 and
Th1 T cells after Ag-driven proliferation (26, 30, 31, 33). As has been previously observed, the poor reactivity to
IL-2 is evidently due to lack of up-regulation of CD25 (IL-2R)
(2, 5, 6, 7, 32). Interestingly, we found that IL-12
administration did increase the expression of CD25 (Fig. 7
). This might
account for our finding that IL-2 can influence homeostatic expansion
when IL-12 is coinjected (Fig. 1). In this case, though, IL-2 appears
to induce the loss of OT-I cells after homeostatic expansion rather
than their expansion; the basis for this is currently uncertain, but
there is considerable evidence that IL-2 not only promotes T cell
growth, but also induces activated and memory T cell death (30, 31, 34).
Our previous work indicated that IL-7 plays a critical role in T cell homeostatic expansion (12). This supports earlier reports showing that depletion of IL-7 (together with IL-4) resulted in a loss of naive CD4 T cells (35). In our hands, supplementary IL-7 did not enhance OT-I homeostatic expansion (W. C. Kieper and S. C. Jameson, data not shown). Although this result suggests that endogenous IL-7 may be at saturating levels for homeostatic expansion, it is possible that the IL-7 doses used in these experiments (250 ng/day for 3 days following T cell transfer) were simply too low to affect expansion; this possibility is currently being explored. Together these data argue that endogenous IL-7 is both necessary and sufficient for T cell homeostatic proliferation and mature T cell survival. The role of IL-7 in homeostatic expansion is hard to determine, because IL-7 is a T cell survival factor (13, 35, 36, 37) but can also support T cell proliferation (38, 39). IL-12 has been shown to enhance CD8 T cell expansion and memory cell production during an immune response in vivo (19). Thus, at present it is unclear whether IL-7 and IL-12 act sequentially or cooperatively in driving homeostatic expansion, a question that will require further investigation. Dissecting the roles of these cytokines on simple T cell survival vs enhanced T cell reactivity will be important to understand the regulation of homeostatic expansion and the potential for its therapeutic manipulation.
There is less information on the factors that might oppose homeostatic
expansion. Our data argue that high dose IL-2 can counter the enhancing
effect of IL-12 on OT-I homeostatic expansion, leading to a loss of T
cell accumulation (Fig. 1). This ties in with previous work suggesting
that IL-2 can restrain as well as promote T cell proliferation
(31, 40, 41, 42, 43), and more specifically, that IL-2 can lead to
loss of memory phenotype CD8 T cells (34). Furthermore,
data from two groups demonstrated that T cell expression of a
dominant-negative TGF- receptor resulted in the massive expansion of
CD8+ lymphocytes (44, 45). Although
the constellation of activation/memory markers induced on these cells
is not identical with that on cells undergoing homeostatic expansion,
it is tempting to speculate that TGF- (which is constitutively
expressed) may dampen homeostatic expansion. Interestingly, studies on
Ag-driven T cell responses suggest that TGF- and IL-12 oppose each
others’ functions (46, 47, 48, 49). Thus, the balance between
these cytokines (and presumably others) may determine the occurrence
and extent of homeostatic expansion.
Chronic antigenic stimulation of T cells can lead to functional
unresponsiveness toward a subsequent Ag challenge, especially in the
absence of costimulation or "danger" cues (50, 51).
Because homeostatic proliferation occurs in response to a continual
presence of self-peptide/MHC ligands and does not appear to involve
classic costimuli (1, 6), it was possible that homeostatic
expansion would generate anergic T cells. Hence another important
aspect of our experiments is the finding that OT-I CD8 T cells that had
undergone homeostatic expansion are fully capable of responding to Ag
stimulation both by proliferation and by in vivo differentiation to
cytolytic effector cells (Figs. 5 and 6). Significantly, the process of
homeostatic expansion apparently allows these T cells to respond to
peptide Ag without adjuvant (evidenced by the proliferative and
differentiative response seen to OVAp alone; Figs. 5 and 6). In
contrast, previous work indicated that naive CD8 T cells were anergized
by peptide Ag alone and required an adjuvant (such as CFA or IL-12)
that was absolutely required for effector cell differentiation
(18, 19). More recent work has shown that memory CD8 T
cells differ in this requirement for adjuvant, and can respond to
peptide alone (C. S. Schmidt and M. F. Mescher, manuscript in
preparation). Overall, then, our data support the finding of others
that homeostatic expansion produces competent cells with memory
function.
Homeostatic expansion has some elements of autoimmunity, in that it involves overt reactivity of T cells to self peptide/MHC ligands, accompanied by proliferation and differentiation. Indeed, in reference to our current data it is noticeable that the pathogenesis of several autoimmune diseases involves IL-12 (52, 53, 54, 55). Because there is extensive evidence that recovery from lymphopenia can induce autoimmune diseases (56, 57, 58, 59), it will be interesting to determine whether IL-12 can exacerbate autoimmunity through its effect on T cell homeostatic expansion.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Immunology, Scripps Research Institute, La Jolla, CA 92037.
3 Address correspondence and reprint requests to Dr. Stephen C. Jameson, University of Minnesota Medical Center, MMC 334, 420 Delaware Street SE, Minneapolis, MN 55455.
4 Abbreviation used in this paper: OVAp, OVA peptide.
Received for publication January 18, 2000. Accepted for publication February 27, 2001.
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C. T. Moses, K. M. Thorstenson, S. C. Jameson, and A. Khoruts Competition for self ligands restrains homeostatic proliferation of naive CD4 T cells PNAS, February 4, 2003; 100(3): 1185 - 1190. [Abstract] [Full Text] [PDF]
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J. Valenzuela, C. Schmidt, and M. Mescher The Roles of IL-12 in Providing a Third Signal for Clonal Expansion of Naive CD8 T Cells J. Immunol., December 15, 2002; 169(12): 6842 - 6849. [Abstract] [Full Text] [PDF]
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A. W. Goldrath, P. V. Sivakumar, M. Glaccum, M. K. Kennedy, M. J. Bevan, C. Benoist, D. Mathis, and E. A. Butz Cytokine Requirements for Acute and Basal Homeostatic Proliferation of Naive and Memory CD8+ T Cells J. Exp. Med., June 17, 2002; 195(12): 1515 - 1522. [Abstract] [Full Text] [PDF]
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C. Tanchot, A. Le Campion, B. Martin, S. Leaument, N. Dautigny, and B. Lucas Conversion of Naive T Cells to a Memory-Like Phenotype in Lymphopenic Hosts Is Not Related to a Homeostatic Mechanism That Fills the Peripheral Naive T Cell Pool J. Immunol., May 15, 2002; 168(10): 5042 - 5046. [Abstract] [Full Text] [PDF]
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A. Le Campion, C. Bourgeois, F. Lambolez, B. Martin, S. Leaument, N. Dautigny, C. Tanchot, C. Penit, and B. Lucas Naive T cells proliferate strongly in neonatal mice in response to self-peptide/self-MHC complexes PNAS, April 2, 2002; 99(7): 4538 - 4543. [Abstract] [Full Text] [PDF]
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J. Geginat, F. Sallusto, and A. Lanzavecchia Cytokine-driven Proliferation and Differentiation of Human Naive, Central Memory, and Effector Memory CD4+ T Cells J. Exp. Med., December 10, 2001; 194(12): 1711 - 1720. [Abstract] [Full Text] [PDF]
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M. Prlic, B. R. Blazar, A. Khoruts, T. Zell, and S. C. Jameson Homeostatic Expansion Occurs Independently of Costimulatory Signals J. Immunol., November 15, 2001; 167(10): 5664 - 5668. [Abstract] [Full Text] [PDF]
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Q. Ge, D. Palliser, H. N. Eisen, and J. Chen Homeostatic T cell proliferation in a T cell-dendritic cell coculture system PNAS, March 5, 2002; 99(5): 2983 - 2988. [Abstract] [Full Text] [PDF]
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A. Le Campion, C. Bourgeois, F. Lambolez, B. Martin, S. Leaument, N. Dautigny, C. Tanchot, C. Penit, and B. Lucas Naive T cells proliferate strongly in neonatal mice in response to self-peptide/self-MHC complexes PNAS, April 2, 2002; 99(7): 4538 - 4543. [Abstract] [Full Text] [PDF]
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