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Cellular and Molecular Life Sciences

, Volume 71, Issue 16, pp 3059–3068 | Cite as

T cell receptor bias for MHC: co-evolution or co-receptors?

  • Sneha Rangarajan
  • Roy A. Mariuzza
Review

Abstract

In contrast to antibodies, which recognize antigens in native form, αβ T cell receptors (TCRs) only recognize antigens as peptide fragments bound to MHC molecules, a feature known as MHC restriction. The mechanism by which MHC restriction is imposed on the TCR repertoire is an unsolved problem that has generated considerable debate. Two principal models have been advanced to explain TCR bias for MHC. According to the germline model, MHC restriction is intrinsic to TCR structure because TCR and MHC molecules have co-evolved to conserve germline-encoded TCR sequences with the ability to bind MHC, while eliminating TCR sequences lacking MHC reactivity. According to the selection model, MHC restriction is not intrinsic to TCR structure, but is imposed by the CD4 and CD8 co-receptors that promote signaling by delivering the Src tyrosine kinase Lck to TCR–MHC complexes through co-receptor binding to MHC during positive selection. Here, we review the evidence for and against each model and conclude that both contribute to determining TCR specificity, although their relative contributions remain to be defined. Thus, TCR bias for MHC reflects not only germline-encoded TCR–MHC interactions but also the requirement to form a ternary complex with the CD4 or CD8 co-receptor that is geometrically competent to deliver a maturation signal to double-positive thymocytes during T cell selection.

Keywords

T cell receptor MHC restriction CD4 CD8 T cell selection Evolution Structure 

Abbreviations

CDR

Complementarity-determining region

ITAM

Immunoreceptor tyrosine activation motif

pMHC

Peptide–MHC

TCR

T cell receptor

Notes

Acknowledgments

This work was supported by grants from the National Institutes of Health (AI036900 and AI073654) to R.A.M.

References

  1. 1.
    Tonegawa S (1983) Somatic generation of antibody diversity. Nature 302:575–581PubMedCrossRefGoogle Scholar
  2. 2.
    Marrack P, Scott-Browne JP, Dai S, Gapin L, Kappler JW (2008) Evolutionarily conserved amino acids that control TCR–MHC interaction. Annu Rev Immunol 26:171–203PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Feng D, Bond CJ, Ely LK, Maynard J, Garcia KC (2007) Structural evidence for a germline-encoded T cell receptor–major histocompatibility complex interaction ‘codon’. Nat Immunol 8:975–983PubMedCrossRefGoogle Scholar
  4. 4.
    Scott-Browne JP, White J, Kappler JW, Gapin L, Marrack P (2009) Germline-encoded amino acids in the αβ T-cell receptor control thymic selection. Nature 458:1043–1046PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Adams JJ, Narayanan S, Liu B, Birnbaum ME, Kruse AC, Bowerman NA, Chen W, Levin AM, Connolly JM, Zhu C, Kranz DM, Garcia KC (2011) T cell receptor signaling is limited by docking geometry to peptide–major histocompatibility complex. Immunity 35:681–693PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Deng L, Langley RJ, Wang Q, Topalian SL, Mariuzza RA (2012) Structural insights into the editing of germ-line-encoded interactions between T-cell receptor and MHC class II by Vα CDR3. Proc Natl Acad Sci USA 109:14960–14965PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Garcia KC (2012) Reconciling views on T cell receptor germline bias for MHC. Trends Immunol 33:429–436PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Yin L, Scott-Browne J, Kappler JW, Gapin L, Marrack P (2012) T cells and their eons-old obsession with MHC. Immunol Rev 250:49–60PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Flajnik MF, Kasahara M (2010) Origin and evolution of the adaptive immune system: genetic events and selective pressure. Nat Rev Genet 11:47–59PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Buslepp J, Wang H, Biddison WE, Appella E, Collins EJ (2003) A correlation between TCR Vα docking on MHC and CD8 dependence: implications for T cell selection. Immunity 19:595–606PubMedCrossRefGoogle Scholar
  11. 11.
    Van Laethem F, Sarafova SD, Park JH, Tai X, Pobezinsky L, Guinter TI, Adoro S, Adams A, Sharrow SO, Feigenbaum L, Singer A (2007) Deletion of CD4 and CD8 coreceptors permits generation of αβT cells that recognize antigens independently of the MHC. Immunity 27:735–750PubMedCrossRefGoogle Scholar
  12. 12.
    Tikhonova AN, Van Laethem F, Hanada K, Lu J, Pobezinsky LA, Hong C, Guinter TI, Jeurling SK, Bernhardt G, Park JH, Yang JC, Sun PD, Singer A (2012) αβ T cell receptors that do not undergo major histocompatibility complex-specific thymic selection possess antibody-like recognition specificities. Immunity 36:79–81PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Van Laethem F, Tikhonova AN, Singer A (2012) MHC restriction is imposed on a diverse T cell repertoire by CD4 and CD8 co-receptors during thymic selection. Trends Immunol 33:437–441PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Yin Y, Wang XX, Mariuzza RA (2012) Crystal structure of a complete ternary complex of T-cell receptor, peptide–MHC, and CD4. Proc Natl Acad Sci USA 109:5405–5410PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Holland SJ, Bartok I, Attaf M, Genolet R, Luescher IF, Kotsiou E, Richard A, Wang E, White M, Coe DJ, Chai JG, Ferreira C, Dyson J (2012) The T-cell receptor is not hardwired to engage MHC ligands. Proc Natl Acad Sci USA 109:E3111–E3118PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Van Laethem F, Tikhonova AN, Pobezinsky LA, Tai X, Kimura MY, Le Saout C, Guinter TI, Adams A, Sharrow SO, Bernhardt G, Feigenbaum L, Singer A (2013) Lck availability during thymic selection determines the recognition specificity of the T cell repertoire. Cell 154:1326–1341PubMedCrossRefGoogle Scholar
  17. 17.
    Rudolph MG, Stanfield RL, Wilson IA (2006) How TCRs bind MHCs, peptides, and coreceptors. Annu Rev Immunol 24:419–466PubMedCrossRefGoogle Scholar
  18. 18.
    Dai S, Huseby ES, Rubtsova K, Scott-Browne J, Crawford F, Macdonald WA, Marrack P, Kappler JW (2008) Cross-reactive T cells spotlight the germline rules for αβ T cell receptor interactions with MHC molecules. Immunity 28:324–334PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Mazza C, Auphan-Anezin N, Gregoire C, Guimezanes A, Kellenberger C, Roussel A, Kearney A, van der Merwe PA, Schmitt-Verhulst AM, Malissen B (2007) How much can a T-cell antigen receptor adapt to structurally distinct antigenic peptides? EMBO J 26:1972–1983PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Garcia KC, Adams JJ, Feng D, Ely LK (2009) The molecular basis of TCR germline bias for MHC is surprisingly simple. Nat Immunol 10:143–147PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Borbulevych OY, Santhanagopolan SM, Hossain M, Baker BM (2011) TCRs used in cancer gene therapy cross-react with MART-1/Melan-A tumor antigens via distinct mechanisms. J Immunol 187:2453–2463PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Colf LA, Bankovich AJ, Hanick NA, Bowerman NA, Jones LL, Kranz DM, Garcia KC (2007) How a single T cell receptor recognizes both self and foreign MHC. Cell 129:135–146PubMedCrossRefGoogle Scholar
  23. 23.
    Yin Y, Li Y, Mariuzza RA (2012) Structural basis for self-recognition by autoimmune T-cell receptors. Immunol Rev 250:32–48PubMedCrossRefGoogle Scholar
  24. 24.
    Hahn M, Nicholson MJ, Pyrdol J, Wucherpfennig KW (2005) Unconventional topology of self peptide–major histocompatibility complex binding by a human autoimmune T cell receptor. Nat Immunol 6:490–496PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Sethi DK, Schubert DA, Anders AK, Heroux A, Bonsor DA, Thomas CP, Sundberg EJ, Pyrdol J, Wucherpfennig KW (2011) A highly tilted binding mode by a self-reactive T cell receptor results in altered engagement of peptide and MHC. J Exp Med 208:91–102PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Liu YC, Miles JJ, Neller MA, Gostick E, Price DA, Purcell AW, McCluskey J, Burrows SR, Rossjohn J, Gras S (2013) Highly divergent T-cell receptor binding modes underlie specific recognition of a bulged viral peptide bound to a human leukocyte antigen class I molecule. J Biol Chem 288:15442–15454PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Mareeva T, Martinez-Hackert E, Sykulev Y (2008) How a T cell receptor-like antibody recognizes major histocompatibility complex-bound peptide. J Biol Chem 283:29053–29059PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Hülsmeyer M, Chames P, Hillig RC, Stanfield RL, Held G, Coulie PG, Alings C, Wille G, Saenger W, Uchanska-Ziegler B, Hoogenboom HR, Ziegler A (2004) A major histocompatibility complex–peptide-restricted antibody and T cell receptor molecules recognize their target by distinct binding modes: crystal structure of human leukocyte antigen (HLA)-A1–MAGE-A1 in complex with FAB-HYB3. J Biol Chem 280:2972–2980PubMedCrossRefGoogle Scholar
  29. 29.
    Scott-Browne JP, Crawford F, Young MH, Kappler JW, Marrack P, Gapin L (2011) Evolutionarily conserved features contribute to alpha/beta T cell receptor specificity. Immunity 35:526–535PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Merkenschlager M, Graf D, Lovatt M, Bommhardt U, Zamoyska R, Fisher AG (1997) How many thymocytes audition for selection? J Exp Med 186:1149–1158PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Zerrahn J, Held W, Raulet DH (1997) The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 88:627–636PubMedCrossRefGoogle Scholar
  32. 32.
    Piepenbrink KH, Blevins SJ, Scott DR, Baker BM (2013) The basis for limited specificity and MHC restriction in a T cell receptor interface. Nat Comm 4:1948CrossRefGoogle Scholar
  33. 33.
    Li QJ, Dinner AR, Qi S, Irvine DJ, Huppa JB, Davis MM, Chakraborty AK (2004) CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse. Nat Immunol 5:791–799PubMedCrossRefGoogle Scholar
  34. 34.
    Artyomov MN, Lis M, Devadas S, Davis MM, Chakraborty AK (2010) CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery. Proc Natl Acad Sci USA 107:16916–16921PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Jiang N, Huang J, Edwards LJ, Liu B, Zhang Y, Beal CD, Evavold BD, Zhu C (2011) Two-stage cooperative T cell receptor–peptide major histocompatibility complex–CD8 trimolecular interactions amplify antigen discrimination. Immunity 34:13–23PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    van der Merwe PA, Cordoba SP (2011) Late arrival: recruiting coreceptors to the T cell receptor complex. Immunity 34:1–3PubMedCrossRefGoogle Scholar
  37. 37.
    Turner JM, Brodsky MH, Irving BA, Levin SD, Perlmutter RM, Littman DR (1990) Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell 60:755–765PubMedCrossRefGoogle Scholar
  38. 38.
    van der Merwe PA, Dushek O (2010) Mechanisms for T cell receptor triggering. Nat Rev Immunol 11:47–55PubMedCrossRefGoogle Scholar
  39. 39.
    Kuhns MS, Davis MM (2007) Disruption of extracellular interactions impairs T cell receptor–CD3 complex stability and signaling. Immunity 26:357–369PubMedCrossRefGoogle Scholar
  40. 40.
    Kuhns MS, Badgandi HB (2012) Piecing together the family portrait of TCR–CD3 complexes. Immunol Rev 250:120–143PubMedCrossRefGoogle Scholar
  41. 41.
    Fernandes RA, Shore DA, Vuong MT, Yu C, Zhu X, Pereira-Lopes S, Brouwer H, Fennelly JA, Jessup CM, Evans EJ, Wilson IA, Davis SJ (2012) The T-cell receptor is a structure capable of initiating signaling in the absence of large conformational rearrangements. J Biol Chem 287:13324–13335PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Call ME, Pyrdol J, Wiedmann M, Wucherpfennig KW (2002) The organizing principle in the formation of the T cell receptor–CD3 complex. Cell 111:967–979PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  1. 1.W.M. Keck Laboratory for Structural BiologyUniversity of Maryland Institute for Bioscience and Biotechnology ResearchRockvilleUSA
  2. 2.Department of Cell Biology and Molecular GeneticsUniversity of MarylandCollege ParkUSA

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