Abstract
The elusive etiology of germline bias of the T cell receptor (TCR) for major histocompatibility complex (MHC) has been clarified by recent 'proof-of-concept' structural results demonstrating the conservation of specific TCR-MHC interfacial contacts in complexes bearing common variable segments and MHC allotypes. We suggest that each TCR variable-region gene product engages each type of MHC through a 'menu' of structurally coded recognition motifs that have arisen through coevolution. The requirement for MHC-restricted T cell recognition during thymic selection and peripheral surveillance has necessitated the existence of such a coded recognition system. Given these findings, a reconsideration of the TCR–peptide-MHC structural database shows that not only have the answers been there all along but also they were predictable by the first principles of physical chemistry.
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References
Rudolph, M.G., Stanfield, R.L. & Wilson, I.A. How TCRs bind MHCs, peptides, and coreceptors. Annu. Rev. Immunol. 24, 419–466 (2006).
Buslepp, J., Wang, H., Biddison, W.E., Appella, E. & Collins, E.J. A correlation between TCR Vα docking on MHC and CD8 dependence: implications for T cell selection. Immunity 19, 595–606 (2003).
Collins, E.J. & Riddle, D.S. TCR-MHC docking orientation: natural selection, or thymic selection? Immunol. Res. 41, 267–294 (2008).
Turner, S.J., Doherty, P.C., McCluskey, J. & Rossjohn, J. Structural determinants of T-cell receptor bias in immunity. Nat. Rev. Immunol. 6, 883–894 (2006).
Tynan, F.E. et al. T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I-bound peptide. Nat. Immunol. 6, 1114–1122 (2005).
Huseby, E.S., Crawford, F., White, J., Marrack, P. & Kappler, J.W. Interface-disrupting amino acids establish specificity between T cell receptors and complexes of major histocompatibility complex and peptide. Nat. Immunol. 7, 1191–1199 (2006).
Marrack, P., Scott-Browne, J.P., Dai, S., Gapin, L. & Kappler, J.W. Evolutionarily conserved amino acids that control TCR-MHC interaction. Annu. Rev. Immunol. 26, 171–203 (2008).
Colf, L.A. et al. How a single T cell receptor recognizes both self and foreign MHC. Cell 129, 135–146 (2007).
Feng, D., Bond, C.J., Ely, L.K., Maynard, J. & Garcia, K.C. Structural evidence for a germline-encoded T cell receptor-major histocompatibility complex interaction 'codon'. Nat. Immunol. 8, 975–983 (2007).
Gras, S., Kjer-Nielsen, L., Burrows, S.R., McCluskey, J. & Rossjohn, J. T-cell receptor bias and immunity. Curr. Opin. Immunol. 20, 119–125 (2008).
Housset, D. & Malissen, B. What do TCR-pMHC crystal structures teach us about MHC restriction and alloreactivity? Trends Immunol. 24, 429–437 (2003).
Wilson, I.A. & Stanfield, R.L. MHC restriction: slip-sliding away. Nat. Immunol. 6, 434–435 (2005).
Jerne, N.K. The somatic generation of immune recognition. Eur. J. Immunol. 1, 1–9 (1971).
Blackman, M. et al. The T cell repertoire may be biased in favor of MHC recognition. Cell 47, 349–357 (1986).
Wu, L.C., Tuot, D.S., Lyons, D.S., Garcia, K.C. & Davis, M.M. Two-step binding mechanism for T-cell receptor recognition of peptide MHC. Nature 418, 552–556 (2002).
Zerrahn, J., Held, W. & Raulet, D.H. The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 88, 627–636 (1997).
Sim, B.C., Zerva, L., Greene, M.I. & Gascoigne, N.R.J. Control of MHC restriction by TCR Vα CDR1 and CDR2. Science 273, 963–966 (1996).
Van Laethem, F. et al. Deletion of CD4 and CD8 coreceptors permits generation of αβT cells that recognize antigens independently of the MHC. Immunity 27, 735–750 (2007).
Venturi, V., Price, D.A., Douek, D.C. & Davenport, M.P. The molecular basis for public T-cell responses? Nat. Rev. Immunol. 8, 231–238 (2008).
Garboczi, D.N. et al. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 384, 134–141 (1996).
Garcia, K.C. et al. An αβ T cell receptor structure at 2.5Å and its orientation in the TCR-MHC complex. Science 274, 209–219 (1996).
Davis, M.M. & Bjorkman, P.J. T-cell antigen receptor genes and T-cell recognition. Nature 334, 395–402 (1988).
Matsui, K. et al. Low affinity interaction of peptide-MHC complexes with T cell receptors. Science 254, 1788–1791 (1991).
Inman, J.K. Theoretical Immunology (eds. Bell, G.I., Perelson, A.S. & Pimbley, G.H.) 243–278 (Marcel Dekker, New York; 1978).
Adams, E.J., Strop, P., Shin, S., Chien, Y.H. & Garcia, K.C. An autonomous CDR3δ is sufficient for recognition of the nonclassical MHC class I molecules T10 and T22 by γδ T cells. Nat. Immunol. 9, 777–784 (2008).
Shin, S. et al. Antigen recognition determinants of γδ T cell receptors. Science 308, 252–255 (2005).
Radaev, S. & Sun, P.D. Structure and function of natural killer cell surface receptors. Annu. Rev. Biophys. Biomol. Struct. 32, 93–114 (2003).
Acha-Orbea, H. et al. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell 54, 263–273 (1988).
Garcia, K.C. & Adams, E.J. How the T cell receptor sees antigen–a structural view. Cell 122, 333–336 (2005).
Fink, P.J. & Bevan, M.J. Positive selection of thymocytes. Adv. Immunol. 59, 99–133 (1995).
Lo Conte, L., Chothia, C. & Janin, J. The atomic structure of protein-protein recognition sites. J. Mol. Biol. 285, 2177–2198 (1999).
Reichmann, D., Rahat, O., Cohen, M., Neuvirth, H. & Schreiber, G. The molecular architecture of protein-protein binding sites. Curr. Opin. Struct. Biol. 17, 67–76 (2007).
Schreiber, G. & Fersht, A.R. Energetics of protein-protein interactions: analysis of the barnase-barstar interface by single mutations and double mutant cycles. J. Mol. Biol. 248, 478–486 (1995).
Richards, F.M. & Richmond, T. Solvents, interfaces and protein structure. Ciba Found. Symp. 60, 23–45 (1977).
Lawrence, M.C. & Colman, P.M. Shape complementarity at protein/protein interfaces. J. Mol. Biol. 234, 946–950 (1993).
Ysern, X., Li, H. & Mariuzza, R.A. Imperfect interfaces. Nat. Struct. Biol. 5, 412–414 (1998).
Wucherpfennig, K.W. et al. Polyspecificity of T cell and B cell receptor recognition. Semin. Immunol. 19, 216–224 (2007).
Boulanger, M.J., Bankovich, A.J., Kortemme, T., Baker, D. & Garcia, K.C. Convergent mechanisms for recognition of divergent cytokines by the shared signaling receptor gp130. Mol. Cell 12, 577–589 (2003).
DeLano, W.L., Ultsch, M.H., de Vos, A.M. & Wells, J.A. Convergent solutions to binding at a protein-protein interface. Science 287, 1279–1283 (2000).
McFarland, B.J. & Strong, R.K. Thermodynamic analysis of degenerate recognition by the NKG2D immunoreceptor: not induced fit but rigid adaptation. Immunity 19, 803–812 (2003).
Manning, T.C. et al. Alanine scanning mutagenesis of an αβ T cell receptor: mapping the energy of antigen recognition. Immunity 8, 413–425 (1998).
Dai, S. et al. Crossreactive T cells spotlight the germline rules for αβ T cell-receptor interactions with MHC molecules. Immunity 28, 324–334 (2008).
Jones, L.L., Colf, L.A., Stone, J.D., Garcia, K.C. & Kranz, D.M. Distinct CDR3 conformations in TCRs determine the level of cross-reactivity for diverse antigens, but not the docking orientation. J. Immunol. 181, 6255–6264 (2008).
Holler, P.D., Chlewicki, L.K. & Kranz, D.M. TCRs with high affinity for foreign pMHC show self-reactivity. Nat. Immunol. 4, 55–62 (2003).
Sami, M. et al. Crystal structures of high affinity human T-cell receptors bound to peptide major histocompatibility complex reveal native diagonal binding geometry. Protein Eng. Des. Sel. 20, 397–403 (2007).
Mazza, C. et al. How much can a T-cell antigen receptor adapt to structurally distinct antigenic peptides? EMBO J. 26, 1972–1983 (2007).
Huseby, E.S. et al. How the T cell repertoire becomes peptide and MHC specific. Cell 122, 247–260 (2005).
Reiser, J.B. et al. CDR3 loop flexibility contributes to the degeneracy of TCR recognition. Nat. Immunol. 4, 241–247 (2003).
Reiser, J.B. et al. Crystal structure of a T cell receptor bound to an allogeneic MHC molecule. Nat. Immunol. 1, 291–297 (2000).
Ganju, R.K., Smiley, S.T., Bajorath, J., Novotny, J. & Reinherz, E.L. Similarity between fluorescein-specific T-cell receptor and antibody in chemical details of antigen recognition. Proc. Natl. Acad. Sci. USA 89, 11552–11556 (1992).
Hahn, M., Nicholson, M.J., Pyrdol, J. & Wucherpfennig, K.W. Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor. Nat. Immunol. 6, 490–496 (2005).
Scott-Browne, J.P. et al. Germline-encoded recognition of diverse glycolipids by natural killer T cells. Nat. Immunol. 8, 1105–1113 (2007).
Borg, N.A., Kjer-Nielsen, L., McCluskey, J. & Rossjohn, J. Structural insight into natural killer T cell receptor recognition of CD1d. Adv. Exp. Med. Biol. 598, 20–34 (2007).
Acknowledgements
We thank J. Kuriyan and D. Kranz for discussions. Supported by the National Health and Medical Research Council (CJ Martin Fellowship to L.K.E.), the Canadian Institute of Health Research (J.J.A.), N.I.H. (D.F., K.C.G.) and the Howard Hughes Medical Institute (K.C.G.).
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Christopher Garcia, K., Adams, J., Feng, D. et al. The molecular basis of TCR germline bias for MHC is surprisingly simple. Nat Immunol 10, 143–147 (2009). https://doi.org/10.1038/ni.f.219
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DOI: https://doi.org/10.1038/ni.f.219
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