Skip to main content

Advertisement

SpringerLink
Log in

Peptide antigens for gamma/delta T cells

  • Multi-author review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

γδ T cells express adaptive antigen receptors encoded by rearranging genes. Their diversity is highest in the small region of TCR V–J junctions, especially in the δ chain, which should enable the γδ TCRs to distinguish differences in small epitopes. Indeed, recognition of small molecules, and of an epitope on a larger protein has been reported. Responses to small non-peptides known as phospho-antigens are multi-clonal yet limited to a single γδ T cell subset in humans and non-human primates. Responses to small peptides are multi-clonal or oligo-clonal, include more than one subset of γδ T cells, and occur in rodents and primates. However, less effort has been devoted to investigate the peptide responses. To settle the questions of whether peptides can be ligands for the γδ TCRs, and whether responses to small peptides might occur normally, peptide binding will have to be demonstrated, and natural peptide ligands identified.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Davis MM, Bjorkman PJ (1988) T cell antigen receptor genes and T cell recognition. Nature 334:395–402

    Article  PubMed  CAS  Google Scholar 

  2. Adams EJ, Chien Y-H, Garcia KC (2005) Structure of a gd T cell receptor in complex with the nonclassical MHC T22. Science 308:227–231

    Article  PubMed  CAS  Google Scholar 

  3. Rock EP, Sibbald PR, Davis MM, Chien Y-H (1994) CDR3 length in antigen-specific immune receptors. J Exp Med 179:323–328

    Article  PubMed  CAS  Google Scholar 

  4. Shin S, El-Diwany R, Schaffert S, Adams EJ, Garcia KC, Pereira P, Chien Y-H (2005) Antigen recognition determinants of gd T cell receptors. Science 308:252–255

    Article  PubMed  CAS  Google Scholar 

  5. Adams EJ, Strop P, Shin S, Chien YH, Garcia KC (2008) An autonomous CDR3delta is sufficient for recognition of the nonclassical MHC class I molecules T10 and T22 by gammadelta T cells. Nat Immunol 9:777–784

    Article  PubMed  CAS  Google Scholar 

  6. Chen H, He X, Wang Z, Wu D, Zhang H, Xu C, He H, Cui L, Ba D, He W (2008) Identification of human T cell receptor gammadelta-recognized epitopes/proteins via CDR3delta peptide-based immunobiochemical strategy. J Biol Chem 283:12528–12537

    Article  PubMed  CAS  Google Scholar 

  7. Bonneville M, O’Brien RL, Born WK (2010) Gammadelta T cell effector functions: a blend of innate programming and acquired plasticity. Nature Rev Immunol 10:467–478

    Article  CAS  Google Scholar 

  8. Jensen KDC, Su X, Shin S, Li L, Youssef S, Yamasaki S, Steinman L, Saito T, Locksley RM, Davis MM, Baumgarth N, Chien Y-H (2008) Thymic selection determines gammadelta T cell effector fate: antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon gamma. Immunity 29:90–100

    Article  PubMed  CAS  Google Scholar 

  9. Lewis J, Girardi M, Roberts SJ, Barbee SD, Hayday AC, Tigelaar RE (2006) Selection of the cutaneous intraepithelial gd + T cell repertoire by a thymic stromal element. Nat Immunol 7:843–850

    Article  PubMed  CAS  Google Scholar 

  10. Boyden LM, Lewis JM, Barbee SD, Bas A, Girardi M, Hayday AC, Tigelaar RE, Lifton RP (2008) Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal gammadelta T cells. Nat Genetics 40:656–662

    Article  CAS  Google Scholar 

  11. Hayday AC (2009) Gammadelta T cells and the lymphoid stress-surveillance response. Immunity 31:184–196

    Article  PubMed  CAS  Google Scholar 

  12. Pluschke G, Rüegg D, Hohlfeld R, Engel AG (1992) Autoaggressive myocytotoxic T lymphocytes expressing an unusual γ/δ T cell receptor. J Exp Med 176:1785–1789

    Article  PubMed  CAS  Google Scholar 

  13. Shimonkevitz R, Colburn C, Burnham JA, Murray RS, Kotzin BL (1993) Clonal expansions of activated γ/δ T cells in recent-onset multiple sclerosis. Proc Natl Acad Sci USA 90:923–927

    Article  PubMed  CAS  Google Scholar 

  14. Roark CL, French JD, Taylor MA, Bendele AM, Born WK, O’Brien RL (2007) Exacerbation of collagen-induced arthritis by oligoclonal, iL-17-producing gd T cells. J Immunol 179:5576–5583

    PubMed  CAS  Google Scholar 

  15. Sim G-K, Augustin A (1991) Extrathymic positive selection of γδ T cells. Vγ4Jγ1 rearrangements with “GxYS” junctions. J Immunol 146:2439–2445

    PubMed  CAS  Google Scholar 

  16. Sim G-K, Augustin A (1991) Dominant expression of the T cell receptor BALB invariant δ (BID) chain in resident pulmonary lymphocytes is due to selection. Eur J Immunol 21:859–861

    Article  PubMed  CAS  Google Scholar 

  17. Morita CT, Beckman EM, Bukowski JF, Tanaka Y, Band H, Bloom BR, Golan DE, Brenner MB (1995) Direct presentation of nonpeptide prenyl pyrophosphate antigens to human γδ T cells. Immunity 3:495–507

    Article  PubMed  CAS  Google Scholar 

  18. Wei H, Huang D, Lai X, Chen M, Zhong W, Wang R, Chen ZW (2008) Definition of APC presentation of phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate to Vgamma2Vdelta2 TCR. J Immunol 181:4798–4806

    PubMed  CAS  Google Scholar 

  19. Russano AM, Agea E, Corazzi L, Postle AD, De Libero G, Porcelli SA, De Benedictis F, Spinozzi F (2006) Recognition of pollen-derived phosphatidyl-ethanolamine by human CD1d-restricted gamma delta T cells. J Allergy Clin Immunol 117:1178–1184

    Article  PubMed  CAS  Google Scholar 

  20. Agea E, Russano A, Bistoni O, Mannucci R, Nicoletti I, Corazzi L, Postle AD, De Libero G, Porcelli SA, Spinozzi F (2005) Human CD1-restricted T cell recognition of lipids from pollens. J Exp Med 202:295–308

    Article  PubMed  CAS  Google Scholar 

  21. Holoshitz J, Vila LM, Keroack BJ, McKinley DR, Bayne NK (1992) Dual antigenic recognition by cloned human γδ T cells. J Clin Invest 89:308–314

    Article  PubMed  CAS  Google Scholar 

  22. Speir JA, Abdel-Motal UM, Jondal M, Wilson IA (1999) Crystal structure of an MHC class I presented glycopeptide that generates carbohydrate-specific CTL. Immunity 10:51–61

    Article  PubMed  CAS  Google Scholar 

  23. Born WK, O’Brien RL (2009) Antigen-restricted gammadelta T-cell receptors? Arch Immunol Ther Exp (Warsz) 57:129–135

    Article  CAS  Google Scholar 

  24. Morita CT, Lee HK, Wang H, Li H, Mariuzza RA, Tanaka Y (2001) Structural features of nonpeptide prenyl pyrophosphates that determine their antigenicity for human gamma delta T cells. J Immunol 167:36–41

    PubMed  CAS  Google Scholar 

  25. Kozbor D, Trinchieri G, Monos DS, Isobe M, Russo G, Haney JA, Zmijewski C, Croce CM (1989) Human TCR-γ+/δ+, CD8+ T lymphocytes recognize tetanus toxoid in an MHC-restricted fashion. J Exp Med 169:1847–1851

    Article  PubMed  CAS  Google Scholar 

  26. Kozbor D, Cassatella MA, Lessin S, Kagan J, Finver S, Faust J, Trinchieri G, Croce CM (1990) Expression and function of gammadelta- and alphabeta-T cell receptor heterodimers on human somatic T cell hybrids. J Immunol 144:3677–3683

    PubMed  CAS  Google Scholar 

  27. Wright A, Lee JE, Link MP, Smith SD, Carroll W, Levy R, Clayberger C, Krensky AM (1989) Cytotoxic T lymphocytes specific for self tumor immunoglobulin express T cell receptor δ chain. J Exp Med 169:1557–1564

    Article  PubMed  CAS  Google Scholar 

  28. O’Brien RL, Happ MP, Dallas A, Palmer E, Kubo R, Born WK (1989) Stimulation of a major subset of lymphocytes expressing T cell receptor γδ by an antigen derived from Mycobacterium tuberculosis. Cell 57:667–674

    Article  PubMed  Google Scholar 

  29. Holoshitz J, Koning F, Coligan JE, De Bruyn J, Strober S (1989) Isolation of CD4− CD8− mycobacteria-reactive T lymphocyte clones from rheumatoid arthritis synovial fluid. Nature 339:226–229

    Article  PubMed  CAS  Google Scholar 

  30. Rust CJJ, Verreck F, Vietor H, Koning F (1990) Specific recognition of staphylococcal enterotoxin A by human T cells bearing receptors with the Vγ9 region. Nature 346:572–574

    Article  PubMed  CAS  Google Scholar 

  31. Johnson RM, Lancki DW, Sperling AI, Dick RF, Spear PG, Fitch FW, Bluestone JA (1992) A murine CD4−, CD8− T cell receptor-γδ T lymphocyte clone specific for Herpes simplex virus glycoprotein I. J Immunol 148:983–988

    PubMed  CAS  Google Scholar 

  32. Harrison LC, Dempsey-Collier M, Kramer DR, Takahashi K (1996) Aerosol insulin induces regulatory CD8 gammadelta T cells that prevent murine insulin-dependent diabetes. J Exp Med 184:2167–2174

    Article  PubMed  CAS  Google Scholar 

  33. Happ MP, Kubo RT, Palmer E, Born WK, O’Brien RL (1989) Limited receptor repertoire in a mycobacteria-reactive subset of γδ T lymphocytes. Nature 342:696–698

    Article  PubMed  CAS  Google Scholar 

  34. Li L, Wu C-Y (2008) CD4+ CD25+ Treg cells inhibit human memory gammadelta T cells to produce IFN-g in response to M. tuberculosis antigen ESAT-6. Blood 111:5629–5636

    Article  PubMed  CAS  Google Scholar 

  35. Brodin P, Rosenkrands I, Andersen P, Cole ST, Brosch R (2004) ESAT-6 proteins: protective antigens and virulence factors? Trends Microbiol 12:500–508

    Article  PubMed  CAS  Google Scholar 

  36. Vidovic D, Roglic M, McKune K, Guerder S, MacKay C, Dembic Z (1989) Qa-1 restricted recognition of foreign antigen by a γδ T-cell hybridoma. Nature 340:646–650

    Article  PubMed  CAS  Google Scholar 

  37. Dembic Z, Vidovic D (1990) Specificity and function of Qa-1 restricted γδ T cells. Res Immunol 141:600–602

    Article  PubMed  CAS  Google Scholar 

  38. Vidovic D, Dembic Z (1991) Qa-1 restricted gamma delta T cells can help B cells. Curr Top Microbiol Immunol 173:239–244

    PubMed  CAS  Google Scholar 

  39. Cady CT, Lahn M, Vollmer M, Tsuji M, Seo SJ, Reardon CL, O’Brien RL, Born WK (2000) Response of murine γδ T cells to the synthetic polypeptide poly-Glu50Tyr50. J Immunol 165:1790–1798

    PubMed  CAS  Google Scholar 

  40. Matis LA, Fry AM, Cron RQ, Cotterman MM, Dick RF, Bluestone JA (1989) Structure and specificity of a class II alloreactive γδ T cell receptor heterodimer. Science 245:746–749

    Article  PubMed  CAS  Google Scholar 

  41. Matis LA, Cron R, Bluestone JA (1987) Major histocompatibility complex-linked specificity of γδ receptor-bearing T lymphocytes. Nature 330:262–264

    Article  PubMed  CAS  Google Scholar 

  42. Bonneville M, Ito K, Krecko EG, Itohara S, Kappes D, Ishida I, Kanagawa O, Janeway JCA, Murphy DB, Tonegawa S (1989) Recognition of a self major histocompatibility complex TL region product by γδ T cell receptors. Proc Natl Acad Sci USA 86:5928–5932

    Article  PubMed  CAS  Google Scholar 

  43. Groh V, Steinle A, Bauer S, Spies T (1998) Recognition of stress-induced MHC molecules by intestinal epithelial γδ T cells. Science 279:1737–1740

    Article  PubMed  CAS  Google Scholar 

  44. Wu J, Groh V, Spies T (2002) T cell antigen receptor engagement and specificity in the recognition of stress-inducible MHC class I-related chains by human epithelial γδ T cells. J Immunol 169:1236–1240

    PubMed  CAS  Google Scholar 

  45. Porcelli S, Brenner MS, Greenstein JK, Balk SP, Terhorst C, Bleicher P (1989) Recognition of cluster of differentiational antigens by human CD4− CD8− cytolytic T lymphocytes. Nature 341:447–450

    Article  PubMed  CAS  Google Scholar 

  46. Huber S, Sartini D, Exley M (2003) Role of CD1d in Coxsackievirus B3-induced myocarditis. J Immunol 170:3147–3153

    PubMed  CAS  Google Scholar 

  47. Fisch P, Malkovsky M, Klein BS, Morrissey LW, Carper SW, Welch WJ, Sondel PM (1990) Human Vγ9/Vδ2 T cells recognize a groEL homolog on Daudi Burkitt’s lymphoma cells. Science 250:1269–1273

    Article  PubMed  CAS  Google Scholar 

  48. Born W, Hall L, Dallas A, Boymel J, Shinnick T, Young D, Brennan P, O’Brien R (1990) Recognition of a peptide antigen by heat shock reactive γδ T lymphocytes. Science 249:67–69

    Article  PubMed  CAS  Google Scholar 

  49. O’Brien RL, Fu Y-X, Cranfill R, Dallas A, Reardon C, Lang J, Carding SR, Kubo R, Born W (1992) Heat shock protein Hsp-60 reactive γδ cells: A large, diversified T lymphocyte subset with highly focused specificity. Proc Natl Acad Sci USA 89:4348–4352

    Article  PubMed  Google Scholar 

  50. Fu Y-X, Kersh G, Vollmer M, Kalataradi H, Heyborne K, Reardon C, Miles C, O’Brien R, Born W (1994) Structural requirements for peptides that stimulate a subset of γδ T cells. J Immunol 152:1578–1588

    PubMed  CAS  Google Scholar 

  51. Fu Y-X, Cranfill R, Vollmer M, van der Zee R, O’Brien RL, Born W (1993) In vivo response of murine γδ T cells to a heat shock protein-derived peptide. Proc Natl Acad Sci USA 90:322–326

    Article  PubMed  CAS  Google Scholar 

  52. Kikuchi GE, Roberts K, Shevach EM, Coligan JE (1992) Gene transfer demonstrates that the Vγ1.1Cγ4Vδ6Cδ T cell receptor is essential for autoreactivity. J Immunol 148:1302–1307

    PubMed  CAS  Google Scholar 

  53. Wang H, Lee HK, Bukowski JF, Li H, Mariuzza RA, Chen ZW, Nam K-H, Morita CT (2003) Conservation of nonpeptide antigen recognition by rhesus monkey Vgamma2Vdelta2 T cells. J Immunol 170:3696–3706

    PubMed  CAS  Google Scholar 

  54. Sarikonda G, Wang H, Puan KJ, Liu XH, Lee HK, Song Y, Distefano MD, Oldfield E, Prestwich GD, Morita CT (2008) Photoaffinity antigens for human gamma delta T cells. J Immunol 181:7738–7750

    PubMed  CAS  Google Scholar 

  55. Blond-Elguindi S, Cwirla SE, Dower WJ, Lipshutz RJ, Sprang SR, Sambrook JF, Gething M-JH (1993) Affinity panning of a library of peptides displayed on bacteriophages reveals the binding specificity of BiP. Cell 75:717–728

    Article  PubMed  CAS  Google Scholar 

  56. Zhang L, Jasinski JM, Kobayashi M, Davenport B, Johnson K, Davidson H, Nakayama M, Haskins K, Eisenbarth GS (2009) Analysis of T cell receptor beta chains that combine with dominant conserved TRAV5D*04 anti-insulin B:9-23 alpha chains. J Autoimmun 33:42–49

    Article  PubMed  Google Scholar 

  57. Zhang L, Jin N, Nakayama M, O’Brien RL, Eisenbarth GS, Born WK (2010) Gamma delta T cell receptors confer autonomous responsiveness to the insulin-peptide B:9-23. J Autoimmun 34:478–484

    Article  PubMed  CAS  Google Scholar 

  58. Abiru N, Wegmann D, Kawasaki E, Gottlieb P, Simone E, Eisenbarth GS (2000) Dual overlapping peptides recognized by insulin peptide B:9–23 T cell receptor AV13S3 T cell clones of the NOD mouse. J Autoimmun 14:231–237

    Article  PubMed  CAS  Google Scholar 

  59. Simone E, Daniel D, Schloot N, Gottlieb P, Babu S, Kawasaki E, Wegmann D, Eisenbarth GS (1997) T cell receptor restriction of diabetogenic autoimmune NOD T cells. Proc Natl Acad Sci USA 94:2518–2521

    Article  PubMed  CAS  Google Scholar 

  60. Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, Yu L, Wegmann DR, Hutton JC, Elliott JF, Eisenbarth GS (2005) Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 435:220–223

    Article  PubMed  CAS  Google Scholar 

  61. Mohan JF, Levisetti MG, Calderon B, Herzog JW, Petzold SJ, Unanue ER (2010) Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes. Nat Immunol 4:350–354

    Article  Google Scholar 

  62. McMenamin C, Pimm C, McKersey M, Holt PG (1994) Regulation of IgE responses to inhaled antigen in mice by antigen-specific γδ T cells. Science 265:1869–1871

    Article  PubMed  CAS  Google Scholar 

  63. McMenamin C, McKersey M, Kühnlein P, Hünig T, Holt PG (1995) γδ T cells down-regulate primary IgE responses in rats to inhaled soluble protein antigens. J Immunol 154:4390–4394

    PubMed  CAS  Google Scholar 

  64. Ke Y, Pearce K, Lake JP, Ziegler HK, Kapp JA (1997) Gamma delta T lymphocytes regulate the induction and maintenance of oral tolerance. J Immunol 158:3610–3618

    PubMed  CAS  Google Scholar 

  65. Wildner G, Hünig T, Thurau SR (1996) Orally induced, peptide-specific γ/δ TCR+ cells suppress experimental autoimmune uveitis. Eur J Immunol 26:2140–2148

    Article  PubMed  CAS  Google Scholar 

  66. Wildner G, Thurau SR, Diedrichs-Mohring M (2004) Gamma–delta T cells as orally induced suppressor cells in rats: in vitro characterization. Ann NY Acad Sci 1029:416–422

    Article  PubMed  CAS  Google Scholar 

  67. Kim HT, Nelson EL, Clayberger C, Sanjanwala M, Sklar J, Krensky AM (1995) γδ T cell recognition of tumor Ig peptide. J Immunol 154:1614–1623

    PubMed  CAS  Google Scholar 

  68. Guo Y, Ziegler HK, Safley SA, Niesel DW, Vaidya S, Klimpel GR (1995) Human T-cell recognition of Listeria monocytogenes: Recognition of listeriolysin O by TcRαβ+ and TcRγδ+ T cells. Infect Immun 63:2288–2294

    PubMed  CAS  Google Scholar 

  69. Luccese G, Stufano A, Trost B, Kusalik A, Kanduc D (2007) Peptidology: short amino acid modules in cell biology and immunology. Amino Acids 33:703–707

    Article  Google Scholar 

  70. Born W, Cady C, Jones-Carson J, Mukasa A, Lahn M, O’Brien R (1999) Immunoregulatory functions of gammadelta T cells. Adv Immunol 71:77–144

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr. George Eisenbarth for reading the manuscript and for helpful suggestions.

Author information

Authors and Affiliations

  1. Integrated Department of Immunology, National Jewish Health, 1400 Jackson Street, GB K409, Denver, CO, 80206, USA

    Willi K. Born, Niyun Jin, Jennifer L. Chain, Yafei Huang, M. Kemal Aydintug & Rebecca L. O’Brien

  2. Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, 80045, USA

    Li Zhang & Maki Nakayama

  3. University of Colorado Denver, Aurora, CO, 80045, USA

    Willi K. Born, Niyun Jin, Jennifer L. Chain, Yafei Huang, M. Kemal Aydintug & Rebecca L. O’Brien

Authors
  1. Willi K. Born
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maki Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Niyun Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jennifer L. Chain
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yafei Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Kemal Aydintug
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rebecca L. O’Brien
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Willi K. Born.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Born, W.K., Zhang, L., Nakayama, M. et al. Peptide antigens for gamma/delta T cells. Cell. Mol. Life Sci. 68, 2335–2343 (2011). https://doi.org/10.1007/s00018-011-0697-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-011-0697-3

Keywords

Search

Navigation