Mature T lymphocytes carrying the conventional αβ T cell receptor (TCR) recognize peptide antigens in the context of MHC class I (CD8+) and MHC class II (CD4+) antigens, respectively. In striking contrast, human γδ T lymphocytes recognize unconventional antigens via their heterodimeric TCR in a non-MHC-restricted fashion. In this brief review, we discuss recent progress in the identification of ligands that are specifically recognized by human γδ T cells. It appears that γδ T cells have evolved to supplement the cellular immune response towards antigens that are not seen by αβ T lymphocytes.

Keywords:
γδ T cells, T cell receptor repertoire, Phosphoantigens, MHC restriction, MHC class I-related chain
1.
Saito H, Kranz DM, Tagagaki Y, Hayday AC, Eisen HN, Tonegawa S: Complete primary structure of a heterodimeric T-cell receptor deduced from cDNA sequences. Nature 1984;309:757–762.
2.
Kabelitz D, Wesch D, Hinz T: γδ T cells, their T cell receptor usage and role in human diseases. Springer Semin Immunopathol 1999;21:55–75.
3.
McVay LD, Carding SR: Generation of human γδ T-cell repertoires. Crit Rev Immunol 1999;19:431–460.
4.
Kabelitz D: Effector functions and control of human γδT-cell activation. Microbes Infect 1999;1:255–261.
5.
Born W, Cady C, Jones-Carson J, Mukasa A, Lahn M, O’Brien R: Immunoregulatory functions of γδ T cells. Adv Immunol 1999;71:77–144.
6.
Hinz T, Wesch D, Halary F, Marx S, Choudhary A, Arden B, Janssen O, Bonneville M, Kabelitz D: Identification of the complete expressed human TCR Vγ repertoire by flow cytometry. Int Immunol 1997;9:1065–1072.
7.
Wesch D, Hinz T, Kabelitz D: Analysis of the TCR Vγ repertoire in healthy donors and HIV-1-infected individuals. Int Immunol 1998;10:1067–1075.
8.
Parker CM, Groh V, Band H, Porcelli SA, Morita G, Fabbi M, Glass D, Strominger JL, Brenner MB: Evidence for extrathymic changes in the T-cell receptor γδ repertoire. J Exp Med 1990;171:1597–1612.
9.
Boullier S, Cochet M, Poccia F, Gougeon M-L: CDR3-independent γδ Vδ1+ T cell expansion in the peripheral blood of HIV-infected persons. J Immunol 1995;154:1418–1431.
10.
Dechanet J, Merville P, Lim A, Retiere C, Pitard V, Lafarge X, Michelson S, Meric C, Hallet M-M, Kourilsky P, Potaux L, Bonneville M, Moreau J-F: Implication of γδ T cells in the human immune response to cytomegalovirus. J Clin Invest 1999;103:1437–1449.
11.
Porcelli S, Brenner MB, Band H: Biology of the human γδ T-cell receptor. Immunol Rev 1991;120:137–183.
12.
Li H, Lebedeva MI, Llera AS, Fields BA, Brenner MB, Mariuzza RA: Structure of the Vδ domain of a human γδ T-cell antigen receptor. Nature 1998;391:502–506.
13.
Rock EP, Sibbald PR, Davis MM, Chien YH: CDR3 length in antigen-specific immune rsponses. J Exp Med 1994;179:323–328.
14.
Schild H, Mavaddat N, Litzenberger C, Ehrich EW, Davis MM, Bluestone JA, Matis L, Draper RK, Chien YH: The nature of major histocompatibility complex recognition by gamma delta T cells. Cell 1994;76:29–37.
15.
Crowley MP, Reich Z, Mavaddat N, Altman JD, Chien Y: The recognition of the nonclassical major histocompatibility complex (MHC) class I molecule, T10, by the gamma delta T cell, G8. J Exp Med 1997;185:1223–1230.
16.
Kozbor D, Trinchieri G, Monos DS, Isobe M, Russo G, Haney JA, Zmijewski C, Croce CM: Human TCR-γ+δ+, CD8+ T lymphocytes recognize tetanus toxoid in an MHC-restricted fashion. J Exp Med 1989;169:1847–1851.
17.
Pfeffer K, Schoel B, Gulle B, Kaufmann SH, Wagner H: Primary responses of human T cells to mycobacteria: A frequent set of gamma/delta T cells are stimulated by protease-resistant ligands. Eur J Immunol 1990;20:1175–1179.
18.
Kabelitz D, Bender A, Schondelmaier S, Schoel B, Kaufmann SH: A large fraction of human peripheral blood gamma/delta+ T cells is activated by Mycobacterium tuberculosis but not by its 65-kD heat shock protein. J Exp Med 1990;171:667–679.
19.
Behr C, Dubois P: Preferential expansion of V gamma 9 V delta 2 T cells following stimulation of peripheral blood lymphocytes with extracts of Plasmodium falciparum. Int Immunol 1992;4:361–366.
20.
Subauste CS, Chung JY, Do D, Koniaris AH, Hunter CA, Montoya JG, Porcelli S, Remington JS: Preferential activation and expansion of human peripheral blood γδ T cells in response to Toxoplasma gondii in vitro and their cytokine production and cytotoxic activity against T. gondii-infected cells. J Clin Invest 1995;96:610–619.
21.
Young JL, Goodall JC, Beacock-Sharp H, Gaston JS: Human γδ T-cell recognition of Yersinia enterocolitica. Immunology 1997;91:503–510.
22.
Poquet Y, Kroca M, Halary F, Stenmark S, Peyrat MA, Bonneville M, Fournie JJ, Sjostedt A: Expansion of Vgamma9 Vdelta2 T cells is triggered by Francisella tularensis-derived phosphoantigens in tularemia but not after tularemia vaccination. Infect Immun 1998;66:2107–2114.
23.
Schoel B, Sprenger S, Kaufmann SH: Phosphate is essential for stimulation of Vgamma9 Vdelta2 T lymphocytes by mycobacterial low molecular weight ligand. Eur J Immunol 1994;24:1886–1892.
24.
Constant P, Davodeau F, Peyrat MA, Poquet Y, Puzo G, Bonneville M, Fournie JJ: Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. Science 1994;264:267–270.
25.
Tanaka Y, Morita CT, Tanaka Y, Nieves E, Brenner MB, Bloom BR: Natural and synthetic non-peptide antigens recognized by human γδ T cells. Nature 1995;375:155–158.
26.
Fournie JJ, Bonneville M: Stimulation of gamma delta T cells by phosphoantigens. Res Immunol 1996;147:338–346.
27.
De Libero G: Sentinel function of broadly reactive human gamma delta T cells. Immunol Today 1997;18:2272–2279.
28.
Tanaka Y, Sano S, Nieves E, de Libero G, Rosa D, Modlin RL, Brenner MB, Bloom BR, Morita CT: Nonpeptide ligands for human gamma delta T cells. Proc Natl Acad Sci USA 1994;91:8175–8179.
29.
Behr C, Poupot R, Peyrat MA, Poquet Y, Constant P, Dubois P, Bonneville M, Fournie JJ: Plasmodium falciparum stimuli for human gamma delta T cells are related to phosphorylated antigens of mycobacteria. Infect Immun 1996;64:2892–2896.
30.
Fischer S, Scheffler A, Kabelitz D: Activation of human gamma delta T cells by heat-treated mistletoe extracts. Immunol Lett 1996;52:69–72.
31.
Betyia ED, Porter JW: Biochemistry of polyisoprenoid biosynthesis. Annu Rev Biochem 1976;45:113–142.
32.
Rohmer M, Knani M, Simonin P, Sutter B, Sahm H: Isoprenoid biosynthesis in bacteria: A novel pathway for early steps leading to isopentenyl diphosphate. Biochem J 1993;295:517–524.
33.
Horbach S, Sahm H, Welle R: Isoprenoid biosynthesis in bacteria: Two different pathways? FEMS Microbiol Lett 1993;111:135–140.
34.
Rohmer M: The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants. Nat Prod Rep 1999;16:565–574.
35.
Jomaa H, Feurle J, Lühs K, Kunzmann V, Tony H-P, Herderich M, Wilhelm M: Vγ9/Vδ2 T cell activation induced by bacterial low molecular mass compounds depends on the 1-deoxy-D-xylulose 5-phosphate pathway of isoprenoid biosynthesis. FEMS Immunol Med Microbiol 1999;25:371–378.
36.
Belmant C, Espinosa E, Poupot R, Peyrat M-A, Guiraud M, Poquet Y, Bonneville M, Fournie JJ: 3-Formyl-1-butyl pyrophosphate: A novel mycobacterial metabolite-activating human γδ T cells. J Biol Chem 1999;274:32079–32084.
37.
Bukowski JF, Morita CT, Brenner MB: Human gamma delta T cells recognize alkylamines derived from microbes, edible plants, and tea: Implications for innate immunity. Immunity 1999;11:57–65.
38.
Sturm E, Braakman E, Fisch P, Vreugdenhil RJ, Sondel P, Bolhuis RLH: Human Vγ9-Vδ2 T cell receptor-γδ lymphocytes show specificity to Daudi Burkitt’s lymphoma cells. J Immunol 1990;145:3202–3208.
39.
Fisch P, Malkovsky M, Kovats S, Sturm E, Braakman E, Klein BS, Voss SD, Morrissey LW, De Mars R, Welch WJ, Bolhuis RLH, Sondel PM: Recognition by human Vγ9/Vδ2 T cells of a GroEL homolog on Daudi Burkitt’s lymphoma cells. Science 1990;250:1269–1273.
40.
L’Faqihi FE, Guiraud M, Dastugue N, Brousset P, Le Bouteiller P, Halary F, Bonneville M, Fournie JJ, Champagne E: Acquisition of a stimulatory activity for Vgamma9/Vdelta2 T cells by a Burkitt’s lymphoma cell line without loss of HLA class I expression. Hum Immunol 1999;60:928–938.
41.
Fisch P, Meuer E, Pende D, Rothenfusser S, Viale O, Kock S, Ferrone S, Fradelizi D, Klein G, Moretta L, Rammensee HG, Boon T, Coulie P, van der Bruggen P: Control of B cell lymphoma recognition via natural killer inhibitory receptors implies a role for human Vγ9/Vδ2 T cells in tumor immunity. Eur J Immunol 1997;27:3368–3379.
42.
Boullier S, Poquet Y, Halary F, Bonneville M, Fournie JJ, Gougeon ML: Phosphoantigen activation induces surface translocation of intracellular CD94/NKG2A class I receptor on CD94-peripheral Vgamma9 Vdelta2 T cells but not on CD94-thymic or mature gammadelta T cell clones. Eur J Immunol 1998;28:3399–3410.
43.
Lang F, Peyrat MA, Constant P, Davodeau F, David-Ameline J, Poquet Y, Vie H, Fournie JJ, Bonneville M: Early activation of human V gamma 9 V delta 2 T cell broad cytotoxicity and TNF production by nonpeptidic mycobacterial ligands. J Immunol 1995;154:5986–5994.
44.
Poccia F, Battistini L, Cipriani B, Mancino G, Martini F, Gougeon ML, Colizzi V: Phosphoantigen-reactive Vgamma9 Vdelta2 T lymphocytes suppress in vitro human immunodeficiency virus type 1 replication by cell-released antiviral factors including CC chemokines. J Infect Dis 1999;180:858–861.
45.
Tsukaguchi K, Balaji KN, Boom WH: CD4+ alpha beta T cell and gamma delta T cell responses to Mycobacterium tuberculosis. Similarities and differences in Ag recognition, cytotoxic effector function, and cytokine production. J Immunol 1995;154:1786–1796.
46.
Bukowski JF, Morita CT, Tanaka Y, Bloom BR, Brenner MB, Band H: V gamma 2 V delta 2 TCR-dependent recognition of non-peptide antigens and Daudi cells analyzed by TCR gene transfer. J Immunol 1995;154:998–1006.
47.
Morita CT, Beckman EM, Bukowski JF, Tanaka Y, Band H, Bloom BR, Golan DE, Brenner MB: Direct presentation of nonpeptide prenyl pyrophosphate antigens to human gamma delta T cells. Immunity 1995;3:495–507.
48.
Deusch K, Luling F, Reich K, Classen M, Wagner H, Pfeffer K: A major fraction of human intraepithelial lymphocytes simultaneously expresses the γ/δ cell receptor, the CD8 accessory molecule and preferentially uses the Vδ1 gene segment. Eur J Immunol 1991;21:1053–1059.
49.
Halstensen TS, Scott H, Brandtzaeg P: Intraepithelial T cells of the TcRγ/δ+ CD8– and Vδ1/Jδ1+ phenotypes are increased in coeliac disease. Scand J Immunol 1989;30:665–672.
50.
Spencer J, Isaacson PG, MacDonald TT, Thomas AJ, Walker-Smith JA: Gamma/delta T cells and the diagnosis of coeliac disease. Clin Exp Immunol 1991;85:109–113.
51.
Bucht A, Söderström K, Esin S, Grunewald J, Hagelberg S, Magnusson I, Wigzell H, Grönberg A, Kiessling R: Analysis of γδ V region usage in normal and diseased human intestinal biopsies and peripheral blood by polymerase chain reaction (PCR) and flow cytometry. Clin Exp Immunol 1995;99:57–64.
52.
McVay LD, Li B, Biancaniello R, Creighton MA, Bachwich D, Lichtenstein G, Rombeau JL, Carding SR: Changes in human mucosal γδ T cell repertoire and function associated with the disease process in inflammatory bowel disease. Mol Med 1997;3:183–203.
53.
Groh V, Steinle A, Bauer S, Spies T: Recognition of stress-induced MHC molecules by intestinal epithelial γδ T cells. Science 1998;279:1737–1740.
54.
Griffith E, Ramsburg E, Hayday A: Recognition by human gut gamma delta cells of stress inducible major histocompatibility molecules on enterocytes. Gut 1998;43:166–167.
55.
Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T: Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci USA 1996;93:12445–12450.
56.
Li P, Willie S, Bauer S, Morris DL, Spies T, Strong RK: Crystal structure of the MHC class homolog MIC-A, a γδ T cell ligand. Immunity 1999;10:577–584.
57.
Groh V, Rhinehart R, Secrist H, Bauer S, Grabstein KH, Spies T: Broad tumor-associated expression and recognition by tumor-derived γδ T cells of MICA and MICB. Proc Natl Acad Sci USA 1999;96:6879–6884.
58.
Vincent MS, Roessner K, Lynch D, Wilson D, Cooper SM, Tschopp J, Sigal SH, Budd RC: Apoptosis of Fashigh CD4+ synovial T cells by Borrelia-reactive Fas-ligandhigh γδ T cells in Lyme arthritis. J Exp Med 1996;184:2109–2117.
59.
Vincent MS, Roessner K, Sellati T, Huston CD, Sigal LH, Behar SM, Radolf JD, Budd RC: Lyme arthritis synovial γδ T cells respond to Borrelia burgdorferi lipoproteins and lipidated hexapeptides. J Immunol 1998;161:5762–5771.
60.
Born W, Hall L, Dallas A, Boymel J, Shinnick T, Young D, Brennan P, O’Brien R: Recognition of a peptide antigen by heat shock reactive γδ T lymphocytes. Science 1990;249:67–69.
61.
Haregewoin A, Singh B, Gupta RS, Finberg RW: A mycobacterial heat shock protein responsive γδ T cell clone also responds to the homologous human heat shock protein: A possible link between infection and autoimmunity. J Infect Dis 1990;163:156–160.
62.
Laad AD, Thomas ML, Fakih AR, Chiplunkar SV: Human gamma delta T cells recognize heat shock protein-60 on oral tumor cells. Int J Cancer 1999;80:709–714.
63.
Holoshitz J, Vila LM, Keroack BJ, McKinley DR, Bayne NK: Dual antigenic recognition by cloned human gamma delta T cells. J Clin Invest 1992;89:308–314.
64.
Pao W, Wen L, Smith AL, Gulbranson-Judge A, Zheng B, Kelsoe G, MacLennan ICM, Owen MJ, Hayday AC: γδ T cell help of B cells is induced by repeated parasitic infection, in the absence of other T cells. Curr Biol 1996;6:1317–1325.
65.
Szczepanik M, Nowak B, Askenase PW, Ptak W: Cross-talk betwen gamma delta T lymphocytes and immune cells in humoral response. Immunology 1998;95:612–617.
66.
Skeen MJ, Ziegler HK: Intercellular interactions and cytokine responsiveness of peritoneal α/β and γ/δ T cells from Listeria-infected mice: Synergistic effects of interleukin 1 and 7 on γ/δ T cells. J Exp Med 1993;178:985–996.
67.
Dieli F, Ptak W, Sireci G, Romano GC, Potestio M, Salerno A, Asherson GL: Cross-talk between V beta 8+ and gamma delta+ T lymphocytes in contact sensitivity. Immunology 1998;93:469–477.
68.
Stinissen P, Zhang J, Vandevyver C, Hermans G, Raus J: Gamma delta T cell responses to activated T cells in multiple sclerosis patients induced by T cell vaccination. J Neuroimmunol 1998;87:94–104.
69.
Collins RA, Werling D, Duggan SE, Bland AP, Parsons KR, Howard CJ: γδ T cells present antigen to CD4+ αβT cells. J Leukoc Biol 1998;63:707–714.
70.
Pechhold K, Wesch D, Schondelmaier S, Kabelitz D: Primary activation of V gamma 9-expressing gamma delta T cells by Mycobacterium tuberculosis. Requirement for Th1-type CD4 T cell help and inhibition by IL-10. J Immunol 1994;152:4984–4992.
71.
Wesch D, Marx S, Kabelitz D: Comparative analysis of alpha beta and gamma delta T cell activation by Mycobacterium tuberculosis and isopentenyl pyrophosphate. Eur J Immunol 1997;27:952–956.
72.
Zuany-Amorim C, Ruffie C, Haile S, Vargaftig BB, Pereira P, Pretolani M: Requirement for γδ T cells in allergic airway inflammation. Science 1998;280:1265–1267.
73.
Lahn M, Kanehio A, Takeda K, Joetham A, Schwarze J, Köhler G, O’Brien R, Gelfand EW, Born W: Negative regulation of airway responsiveness that is dependent on γδ T cells and independent of αβ T cells. Nat Med 1999;5:1150–1156.
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