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CUTTING EDGE |
,§
*
Cellular Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
Neurocrine Biosciences, Inc., San Diego, CA 92121;
Torrey Pines Institute for Molecular Studies, San Diego, CA 92121;
§
Multiple Peptide Systems, San Diego, CA 92121; and
¶
Department of Neurology, University of Maryland at Baltimore Medical School, Baltimore, MD 21201
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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When the structures of two class I-restricted TCRs and their complexes
with antigenic peptide and MHC were resolved (11, 12), it became clear
that the portion of the TCR that contacts the MHC/peptide complex forms
a rather flat interface, with only one pocket where the V
and Vß
chains join each other. Surprisingly, most of the contact surface
between TCR and MHC/peptide complex is made up by TCR and MHC molecule
directly rather than between the TCR and the peptide. For one of the
two TCR, it was found that peptide residue Y5 which contacted the TCR
in the pocket could be replaced by the nonconservative substitution A
without losing the ability to form stable complexes (13). These
biophysical observations indicate that a preexisting affinity between
TCR and MHC may allow for at least part of the flexibility in TCR Ag
recognition.
To address the question as to how many modifications of the antigenic peptide a TCR can tolerate and to define rules for how multisubstituted peptides are recognized, we studied in detail the responses of three well-characterized human CD4+, HLA class II-restricted autoreactive T cell clones (TCC). The response of the TCC to a large panel of single aa-substituted peptides was determined and compared with the response to multisubstituted peptides.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Myelin basic protein peptide 87–99 (MBP (87–99)), VHFFKNIVTPRTP, and derivatives thereof were synthesized using Merrifield’s solid phase methodology as described (14). All peptides have purity of >95%. The one-letter amino acid code is used throughout the article.
T cell clones
TCC were generated from PBL by limiting dilution technique as
described (15). Clonality was proven by analysis of the V and Vß
TCR chain expression using family-specific primers for RT-PCR as
described. The restriction elements are DRB5*0101 for TCC TL3A6,
DRB1*0404 for TCC GP52, and DRB1*1302 for TCC GDBP.
T cell proliferation
Cell proliferation was measured by standard [3H]TdR incorporation as described (15). TCC were rested for 8 to 12 days, washed, and resuspended at 1 x 105 cells/ml in complete medium Iscove’s modified Dulbeccols medium containing 5% human serum, 1% penicillin/streptomycin, 0.2% gentamicin (all Whittaker Bioproducts, Gaithersburg, MD)). One hundred microliters of this cell suspension were added to each well of 96-well U-bottom plates containing 5 x 104 irradiated (3000 R) PBL and varying concentrations of peptide. Cells were cultured for 72 h at 37°C. During the last 6 h of culture, 1 µCi of [3H]TdR was added to each well. Cells were then harvested, and incorporated radioactivity was measured by scintillation counting. For the antagonist assays (15), PBL were prepulsed with 25 µg/ml MBP (87–99), washed twice, and then incubated with different concentrations of antagonist peptide.
CTL assay
CTL assays were performed as reported previously (16). Target cells (5 x 105) were labeled overnight at 37°C in 500 µl of CTL medium (RPMI + 5% FCS + 1% glutamine) with 50 µCi of 51Cr (DuPont-New England Nuclear, Boston, MA). 51Cr-labeled cells were incubated with either no Ag or 100 µg/ml peptide for 2 h and washed twice. Targets (2 x 103) were plated into 96-well U-bottom microtiter plates containing 1 x 104 or 1 x 105 T cells (E:T ratios, 5:1 and 50:1). After 4 h of incubation (37°C), supernatants were counted in a gamma counter (ME Plus, ICN Micromedic, Huntsville, AL). Specific lysis was calculated according to the following formula: 100% x [test release (cpm) - spontaneous release (cpm)]/[total incorporation (cpm) - spontaneous release (cpm)].
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previously described human CD4+ TCC (15) were
tested for their response to a large panel of modified ligands derived
from MBP (87–99). First, the TCC were assayed for their proliferative
response to a set of single aa-substituted peptides based on their
native ligand MBP (87–99). Within the core sequence of the epitope,
which was defined by the response to truncated variants (Table I
), at least eight substitutions (either
nonconservative or conservative) and, for positions outside of the
core, at least five substitutions were used for each aa within the MBP
(87–99) peptide. The dose-response curve to the set of modified
ligands was compared with that obtained with MBP (87–99). As shown for
position 92 (N in the native peptide) (Fig. 1), some modifications completely
abrogated the response (i.e., F for TCC TL3A6), whereas others
decreased the response by 1 (i.e., D for TCC GDBP) or 2 (i.e., Q for
TCC GDBP) orders of magnitude. In agreement with our previous studies,
we also identified modifications resulting in ligands that were as
potent as (i.e., G for TCC TL3A6) or even more potent than (i.e., L for
TCC TL3A6) the native ligand (16, 17). Such superagonist peptides
elicited a similar functional response at Ag concentrations up to 2
orders of magnitude lower than the native ligand.
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). The chemical properties of the modifications were related to
the T cell response elicited. In some instances, only conservative
substitutions were tolerated. For TCC TL3A6, R in position 97 could be
replaced only by the highly conservative aa K, which shares charge and
size. The replacement by H, which differs mainly by its aromatic ring,
was not tolerated, nor was any other substitution. Similarly, TCC GDBP
only tolerated conservative aa L, Y, and W to replace F in position 89.
Effects of modifications of P in position 96 were more complex. While
TCC TL3A6 responded partially to F, TCC GP52 was stimulated only by A,
suggesting that the kink induced by P was important (imitated by the
bulky aromatic ring of F) in the first case, whereas the size and the
lack of polarity defined the tolerated aa in the latter case. Another
example of structural influences on recognition was observed at
position 88 for TCC GDBP, which best tolerated those aa that shared an
aromatic ring (F, Y). However, in several instances, we did not observe
a relationship between the chemical characteristics of aa side chains
and the influence on peptide recognition. As shown for TCC GDBP in
position 95, K induced a stronger response than the native aa T; N a
similar response; E, I, and S a reduced response; and G and A an even
weaker response (Table I). For TCC GP52, the chemically unrelated aa F
and A were tolerated in position 91 as replacement for K, whereas the
most conservative aa R was not (Table I). These findings demonstrate
that the chemical properties and the functional response relate to each
other in some positions (18), but not in others. With respect to the
location relative to the epitope core, although positions outside of
the core can negatively or positively affect recognition, the overall
effects are minor and fade with increasing distance from the core
(Table I). The number of tolerated aa was lower in core positions,
although many alterations resulted in productive ligands (13
substitutions of 85 tolerated by TCC TL3A6, 28 of 84 by TCC GDBP, and
24 of 85 by TCC GP52) (Table I). T cell responses to multisubstituted peptides are predictable
Next, we addressed how combinations of multiple aa modifications
within one peptide would affect recognition. The combination of two
positive alterations resulted in an even stronger ligand for TCC TL3A6
(Fig. 2 first panel),
whereas the combination of a negative and a positive alteration
resulted in a peptide with the same potency as MBP (87–99) (Fig. 2, second panel). Peptides with aa modifications that
led to altered functional T cell responses such as antagonism or
partial activation (15) were turned into stimulatory ligands when
multiple positive modifications were introduced (Fig. 2, third and fourth panels). Interestingly,
for TCC TL3A6, ligands that elicited partial agonist responses (anergy
and IL-2R up-regulation in the absence of proliferation) turned into
stronger ligands than peptides with mixed partial agonist (anergy
induction in the absence of proliferation)/antagonist properties (Fig. 2; Table II) or even pure antagonist
properties (Table II) after introduction of multiple superagonist
modifications. These findings support the concept of a hierarchy in the
stimulatory capacity that groups antagonists below partial agonists and
full agonists. However, it also indicates that the induction of
antagonism or partial agonism relates to the affinity of the TCR for
the entire MHC/peptide complex (19) rather than being a feature of
modifications at particular positions of the ligand (18, 20).
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). The proliferative response was determined and the
EC20 defined for each peptide. The sum of the relative
changes induced by multiple substitutions was compared with the effect
of single aa modifications (Table II). With one exception, the
response to single aa-modified peptides permitted the prediction of the
relative changes in the response to a multisubstituted peptide with
remarkable accuracy (within the range of 1 order of magnitude). Identification of agonist ligands with no sequence homology to MBP (87–99)
Following these observations and on the basis of the response of
TCC GP52 to single aa mutations, we designed a peptide that differed
from the MBP (87–99) peptide in all 13 positions. The final peptide
consisted of four positive substitutions (L89, L90, A96, K98), three
neutral substitutions (G87, G88, A99), four substitutions that induced
a slight decrease in the response (H92, V93, I94, S95), and two aa that
strongly decreased the response (A91, K97). The resulting peptide
induced proliferation at concentrations 2 to 3 orders of magnitude
higher than that of MBP (87–99), within a range predicted by adding
the effects of single aa modifications (Fig. 3A). The recognition
was confirmed by CTL assays, which showed that the TCC lysed
MHC-matched target cells pulsed with the nonhomologous peptide, but not
the mismatched targets loaded with the same peptide (Fig. 3B). This proved that the recognition of the peptide
was dependent on MHC presentation, excluding unspecific mechanisms of T
cell activation by the peptide. Similar results were obtained for TCC
TL3A6. On the basis of results obtained with single amino acid
modifications (Table I) and a decapeptide combinatorial library in the
positional scanning format (16) (B. Hemmer, manuscript in preparation),
we identified a peptide ligand (WYALLPSCKG) that stimulated the TCC at
high Ag concentration (EC20 2 orders of magnitude higher
than with the MBP peptide) (Fig. 3C). This ligand
incorporated three neutral aa modifications (W89, Y90, G98), three that
increased (L92, P94, K97), and four that decreased the response (A91,
L93, S95, C96).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) and other experimental systems (18, 22), this strategy
allows the reliable identification of multisubstituted cross-reacting
Ags; 4) as a result of this approach, stimulatory peptides can be
identified, with aa sequences entirely different from that of the Ag
used to establish and propagate the TCC. Considering the large contact surface between TCR and MHC demonstrated by the crystal structure (11, 12) and the independent contribution of each aa to the stimulatory capacity of the peptide, we propose a model for the interaction of the TCR with the MHC/peptide complex. The TCR itself has a defined affinity to the MHC molecule that may even be sufficient for T cell activation as demonstrated in some models of peptide-independent allorecognition (23). In most cases, however, the interaction requires the contribution of the antigenic peptide. The additive contribution (positive, negative, or neutral) of each aa in the sequence to (1) peptide binding to the MHC (21) and (2) affinity of the complex for the TCR is indeed consistent with the linear structure of the MHC-bound antigenic peptide. Therefore, each residue of the peptide can influence ligand density on the APC (by MHC binding) and the overall affinity of the MHC/peptide complex to the TCR. Although aa in MHC binding position contribute more to MHC affinity and less to TCR affinity, whereas aa in TCR contact positions add more to TCR affinity than to MHC binding, each aa contributes to both interactions, thus ultimately determining the number of engaged TCR molecules and the functional activation of the T cell (24, 25). This integration model for TCR Ag recognition is strongly supported by recent reports, which demonstrate that a set of combinatorial peptide libraries each with only one defined aa allow the identification of high potency ligands for these (B. Hemmer, C. Pinilla, B. Gran, N. Ling, P. Conlon, H. F. McFarland, R. Houghten, and R. Martin, manuscript in preparation) and other TCC (16, 26). Although certain aa in the peptide sequence seem to be more important than others, none of them is strictly required for T cell recognition. Consistent with observations regarding other protein-protein interactions (27), we propose for the interaction of the TCR with its ligand that the combination of positive and negative effects of individual aa in the antigenic peptide determines whether the resulting affinity of the MHC/peptide ligand for the TCR is high enough to trigger TCR-dependent signaling events (16).
This flexibility in TCR Ag recognition may explain recent findings in thymic selection that (1) unrelated peptides can select the same TCR (28) and (2) the same MHC/peptide complex can select T cells with very different Ag specificities (29).
With respect to molecular mimicry, our results clarify why a search algorithm for mimicry peptides that incorporated only few aa in specific MHC and TCR contact positions identified only a small number of cross-reactive peptides and why the predictive value of this approach was limited (8). The concept of T cell recognition discussed here argues for extensive degeneracy in TCR-MHC/peptide interactions and seems to question the exquisite specificity of the cellular immune response. Although many ligands are indeed recognized by a specific TCR, it should be noted that under physiologic conditions only the few best fitting MHC/peptide complexes will fully activate a given T cell. During natural immune responses such as those to viral infections, only these high affinity interactions will lead to expansion of T cells. These observations not only extend previous models for TCR Ag recognition but also provide new directions for examining cross-reactivity between Ags during autoimmune responses.
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Acknowledgments |
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Footnotes |
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2 B.H. and M.V. contributed equally to the study.
3 Address correspondence and reprint requests to Dr. Roland Martin, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bldg. 10 Room 5B16, 10 Center Drive MSC 1400, Bethesda, MD 20892-1400. E-mail address:
4 Abbreviations used in this paper: aa, amino acid; TCC, T cell clone; MBP, myelin basic protein peptide 87–99; EC20, concentration required to induce 20% of the maximal response.
Received for publication October 31, 1997. Accepted for publication February 11, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß T-cell receptor structure at 2.5 A and its orientation in the TCR-MHC complex. Science 274:209./ß with an antigenic Tax peptide from human T lymphotropic virus type 1 and the class I MHC molecule HLA-A2. J. Immunol. 157:5403.[Abstract]
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D. Hudrisier, J. Riond, O. Burlet-Schiltz, M. G. von Herrath, H. Lewicki, B. Monsarrat, M. B. A. Oldstone, and J. E. Gairin Structural and Functional Identification of Major Histocompatibility Complex Class I-restricted Self-peptides as Naturally Occurring Molecular Mimics of Viral Antigens. POSSIBLE ROLE IN CD8+ T CELL-MEDIATED, VIRUS-INDUCED AUTOIMMUNE DISEASE J. Biol. Chem., May 25, 2001; 276(22): 19396 - 19403. [Abstract] [Full Text] [PDF]
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