Skip to main content

Advertisement

SpringerLink
Log in

γδ T cells in rheumatic diseases: from fundamental mechanisms to autoimmunity

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

The innate and adaptive arms of the immune system tightly regulate immune responses in order to maintain homeostasis and host defense. The interaction between those two systems is critical in the activation and suppression of immune responses which if unchecked may lead to chronic inflammation and autoimmunity. γδ T cells are non-conventional lymphocytes, which express T cell receptor (TCR) γδ chains on their surface and straddle between innate and adaptive immunity. Recent advances in of γδ T cell biology have allowed us to expand our understanding of γδ T cell in the dysregulation of immune responses and the development of autoimmune diseases. In this review, we summarize current knowledge on γδ T cells and their roles in skin and joint inflammation as commonly observed in rheumatic diseases.

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.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Roberts S, Girardi M (2008) Conventional and unconventional T Cells. In: Gaspari AA, Tyring SK (eds) Clinical and Basic Immunodermatology. Springer, London, pp 85–104. https://doi.org/10.1007/978-1-84800-165-7_6

    Chapter  Google Scholar 

  2. Nielsen MM, Witherden DA, Havran WL (2017) γδ T cells in homeostasis and host defence of epithelial barrier tissues. Nat Rev Immunol 17(12):733–745. https://doi.org/10.1038/nri.2017.101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vrieling M, Santema W, Van Rhijn I, Rutten V, Koets A (2012) γδ T cell homing to skin and migration to skin-draining lymph nodes is CCR7 independent. J Immunol 188(2):578–584. https://doi.org/10.4049/jimmunol.1101972

    Article  CAS  PubMed  Google Scholar 

  4. Su D, Shen M, Li X, Sun L (2013) Roles of γδ T cells in the pathogenesis of autoimmune diseases. Clin Dev Immunol 2013:985753–985753. https://doi.org/10.1155/2013/985753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tyler CJ, Doherty DG, Moser B, Eberl M (2015) Human Vγ9/Vδ2 T cells: innate adaptors of the immune system. Cell Immunol 296(1):10–21. https://doi.org/10.1016/j.cellimm.2015.01.008

    Article  CAS  PubMed  Google Scholar 

  6. Wang L, Das H, Kamath A, Bukowski JF (2001) Human Vγ2Vδ2 T cells produce IFN-γ and TNF-α with an on/off/on cycling pattern in response to live bacterial products. J Immunol 167(11):6195–6201. https://doi.org/10.4049/jimmunol.167.11.6195

    Article  CAS  PubMed  Google Scholar 

  7. Glatzel A, Wesch D, Schiemann F, Brandt E, Janssen O, Kabelitz D (2002) Patterns of chemokine receptor expression on peripheral blood γδ T lymphocytes: strong expression of CCR5 is a selective feature of Vδ2/Vγ9 γδ T cells. J Immunol 168(10):4920–4929. https://doi.org/10.4049/jimmunol.168.10.4920

    Article  CAS  PubMed  Google Scholar 

  8. Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, Ahlfors H, Wilhelm C, Tolaini M, Menzel U, Garefalaki A, Potocnik AJ, Stockinger B (2011) Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 12(3):255–263. https://doi.org/10.1038/ni.1993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Malik S, Want MY, Awasthi A (2016) The emerging roles of Gamma-Delta T cells in tissue inflammation in experimental autoimmune encephalomyelitis. Front Immunol 7:14–14. https://doi.org/10.3389/fimmu.2016.00014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Casetti R, Agrati C, Wallace M, Sacchi A, Martini F, Martino A, Rinaldi A, Malkovsky M (2009) Cutting edge: TGF-beta1 and IL-15 Induce FOXP3+ gammadelta regulatory T cells in the presence of antigen stimulation. J Immunol 183(6):3574–3577. https://doi.org/10.4049/jimmunol.0901334

    Article  CAS  PubMed  Google Scholar 

  11. Huang Y, Jin N, Roark CL, Aydintug MK, Wands JM, Huang H, O'Brien RL, Born WK (2009) The influence of IgE-enhancing and IgE-suppressive gammadelta T cells changes with exposure to inhaled ovalbumin. J Immunol 183(2):849–855. https://doi.org/10.4049/jimmunol.0804104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A (2010) Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol 130(5):1373–1383. https://doi.org/10.1038/jid.2009.399

    Article  CAS  PubMed  Google Scholar 

  13. Cai Y, Shen X, Ding C, Qi C, Li K, Li X, Jala Venkatakrishna R, H-g Z, Wang T, Zheng J, Yan J (2011) Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity 35(4):596–610. https://doi.org/10.1016/j.immuni.2011.08.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guggino G, Ciccia F, Di Liberto D, Lo Pizzo M, Ruscitti P, Cipriani P, Ferrante A, Sireci G, Dieli F, Fourniè JJ, Giacomelli R, Triolo G (2016) Interleukin (IL)-9/IL-9R axis drives γδ T cells activation in psoriatic arthritis patients. Clin Exp Immunol 186(3):277–283. https://doi.org/10.1111/cei.12853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ito Y, Usui T, Kobayashi S, Iguchi-Hashimoto M, Ito H, Yoshitomi H, Nakamura T, Shimizu M, Kawabata D, Yukawa N, Hashimoto M, Sakaguchi N, Sakaguchi S, Yoshifuji H, Nojima T, Ohmura K, Fujii T, Mimori T (2009) γδ T cells are the predominant source of interleukin-17 in affected joints in collagen-induced arthritis, but not in rheumatoid arthritis. Arthritis Rheum 60(8):2294–2303. https://doi.org/10.1002/art.24687

    Article  CAS  PubMed  Google Scholar 

  16. Bank I, Cohen L, Mouallem M, Farfel Z, Grossman E, Ben-Nun A (2002) gammadelta T cell subsets in patients with arthritis and chronic neutropenia. Ann Rheum Dis 61(5):438–443. https://doi.org/10.1136/ard.61.5.438

    Article  PubMed  PubMed Central  Google Scholar 

  17. Muro R, Takayanagi H, Nitta T (2019) T cell receptor signaling for γδT cell development. Inflamm Regen 39(1):6. https://doi.org/10.1186/s41232-019-0095-z

    Article  PubMed  PubMed Central  Google Scholar 

  18. Bottino C, Tambussi G, Ferrini S, Ciccone E, Varese P, Mingari MC, Moretta L, Moretta A (1988) Two subsets of human T lymphocytes expressing gamma/delta antigen receptor are identifiable by monoclonal antibodies directed to two distinct molecular forms of the receptor. J Exp Med 168(2):491–505

    Article  CAS  Google Scholar 

  19. Wesch D, Hinz T, Kabelitz D (1998) Analysis of the TCR Vgamma repertoire in healthy donors and HIV-1-infected individuals. Int Immunol 10(8):1067–1075

    Article  CAS  Google Scholar 

  20. Davey MS, Willcox CR, Hunter S, Kasatskaya SA, Remmerswaal EBM, Salim M, Mohammed F, Bemelman FJ, Chudakov DM, Oo YH, Willcox BE (2018) The human Vδ2(+) T-cell compartment comprises distinct innate-like Vγ9(+) and adaptive Vγ9(-) subsets. Nat Commun 9(1):1760–1760. https://doi.org/10.1038/s41467-018-04076-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. O'Brien RL, Born WK (2010) gammadelta T cell subsets: a link between TCR and function? Semin Immunol 22(4):193–198. https://doi.org/10.1016/j.smim.2010.03.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wu D, Wu P, Qiu F, Wei Q, Huang J (2017) Human γδT-cell subsets and their involvement in tumor immunity. Cell Mol Immunol 14(3):245–253. https://doi.org/10.1038/cmi.2016.55

    Article  CAS  PubMed  Google Scholar 

  23. Davey MS, Willcox CR, Joyce SP, Ladell K, Kasatskaya SA, McLaren JE, Hunter S, Salim M, Mohammed F, Price DA, Chudakov DM, Willcox BE (2017) Clonal selection in the human Vδ1 T cell repertoire indicates γδ TCR-dependent adaptive immune surveillance. Nat Commun 8:14760–14760. https://doi.org/10.1038/ncomms14760

    Article  PubMed  PubMed Central  Google Scholar 

  24. Mangan BA, Dunne MR, O'Reilly VP, Dunne PJ, Exley MA, O'Shea D, Scotet E, Hogan AE, Doherty DG (2013) Cutting edge: CD1d restriction and Th1/Th2/Th17 cytokine secretion by human Vδ3 T cells. J Immunol 191(1):30–34. https://doi.org/10.4049/jimmunol.1300121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang L, Xu M, Wang C, Zhu L, Hu J, Chen S, Wu X, Li B, Li Y (2014) The feature of distribution and clonality of TCR γ/δ subfamilies T cells in patients with B-cell non-Hodgkin lymphoma. J Immunol Res 2014:241246–241246. https://doi.org/10.1155/2014/241246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dimova T, Brouwer M, Gosselin F, Tassignon J, Leo O, Donner C, Marchant A, Vermijlen D (2015) Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire. Proc Natl Acad Sci U S A 112(6):E556–E565. https://doi.org/10.1073/pnas.1412058112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vermijlen D, Gatti D, Kouzeli A, Rus T, Eberl M (2018) γδ T cell responses: how many ligands will it take till we know? Semin Cell Dev Biol 84:75–86. https://doi.org/10.1016/j.semcdb.2017.10.009

    Article  CAS  PubMed  Google Scholar 

  28. Willcox CR, Pitard V, Netzer S, Couzi L, Salim M, Silberzahn T, Moreau J-F, Hayday AC, Willcox BE, Déchanet-Merville J (2012) Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor. Nat Immunol 13:872. https://doi.org/10.1038/ni.2394

    Article  CAS  PubMed  Google Scholar 

  29. Caccamo N, La Mendola C, Orlando V, Meraviglia S, Todaro M, Stassi G, Sireci G, Fournié JJ, Dieli F (2011) Differentiation, phenotype, and function of interleukin-17–producing human Vγ9Vδ2 T cells. Blood 118(1):129–138. https://doi.org/10.1182/blood-2011-01-331298

    Article  CAS  PubMed  Google Scholar 

  30. Eberl M, Roberts GW, Meuter S, Williams JD, Topley N, Moser B (2009) A rapid crosstalk of human γδ T cells and monocytes drives the acute inflammation in bacterial infections. PLoS Pathog 5(2):e1000308. https://doi.org/10.1371/journal.ppat.1000308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Eberl M, Moser B (2009) Monocytes and γδ T cells: close encounters in microbial infection. Trends Immunol 30(12):562–568. https://doi.org/10.1016/j.it.2009.09.001

    Article  CAS  PubMed  Google Scholar 

  32. Davey MS, Lin C-Y, Roberts GW, Heuston S, Brown AC, Chess JA, Toleman MA, Gahan CGM, Hill C, Parish T, Williams JD, Davies SJ, Johnson DW, Topley N, Moser B, Eberl M (2011) Human neutrophil clearance of bacterial pathogens triggers anti-microbial γδ T cell responses in early infection. PLoS Pathog 7(5):e1002040. https://doi.org/10.1371/journal.ppat.1002040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wu Y, Wu W, Wong WM, Ward E, Thrasher AJ, Goldblatt D, Osman M, Digard P, Canaday DH, Gustafsson K (2009) Human γδ T cells: a lymphoid lineage cell capable of professional phagocytosis. J Immunol 183(9):5622–5629. https://doi.org/10.4049/jimmunol.0901772

    Article  CAS  PubMed  Google Scholar 

  34. Brandes M, Willimann K, Moser B (2005) Professional antigen-presentation function by human γδ T cells. Science 309(5732):264–268. https://doi.org/10.1126/science.1110267

    Article  CAS  PubMed  Google Scholar 

  35. Shen Y, Zhou D, Qiu L, Lai X, Simon M, Shen L, Kou Z, Wang Q, Jiang L, Estep J, Hunt R, Clagett M, Sehgal PK, Li Y, Zeng X, Morita CT, Brenner MB, Letvin NL, Chen ZW (2002) Adaptive immune response of Vgamma2Vdelta2+ T cells during mycobacterial infections. Science (New York, NY) 295(5563):2255–2258. https://doi.org/10.1126/science.1068819

    Article  CAS  Google Scholar 

  36. Brandes M, Willimann K, Lang AB, Nam K-H, Jin C, Brenner MB, Morita CT, Moser B (2003) Flexible migration program regulates γδ T-cell involvement in humoral immunity. Blood 102(10):3693–3701. https://doi.org/10.1182/blood-2003-04-1016

    Article  CAS  PubMed  Google Scholar 

  37. Horner AA, Jabara H, Ramesh N, Geha RS (1995) gamma/delta T lymphocytes express CD40 ligand and induce isotype switching in B lymphocytes. J Exp Med 181(3):1239–1244

    Article  CAS  Google Scholar 

  38. Bansal RR, Mackay CR, Moser B, Eberl M (2012) IL-21 enhances the potential of human γδ T cells to provide B-cell help. Eur J Immunol 42(1):110–119. https://doi.org/10.1002/eji.201142017

    Article  CAS  PubMed  Google Scholar 

  39. Petrasca A, Melo AM, Breen EP, Doherty DG (2018) Human Vδ3+ γδ T cells induce maturation and IgM secretion by B cells. Immunol Lett 196:126–134. https://doi.org/10.1016/j.imlet.2018.02.002

    Article  CAS  PubMed  Google Scholar 

  40. Vermijlen D, Ellis P, Langford C, Klein A, Engel R, Willimann K, Jomaa H, Hayday AC, Eberl M (2007) Distinct cytokine-driven responses of activated blood gammadelta T cells: insights into unconventional T cell pleiotropy. J Immunol 178(7):4304–4314

    Article  CAS  Google Scholar 

  41. Born WK, Huang Y, Reinhardt RL, Huang H, Sun D, O’Brien RL (2017) γδ T cells and B cells. In: Alt FW (ed) Adv Immunol, vol 134. Academic Press, pp 1–45. https://doi.org/10.1016/bs.ai.2017.01.002

    Google Scholar 

  42. Caccamo N, Battistini L, Bonneville M, Poccia F, Fournié JJ, Meraviglia S, Borsellino G, Kroczek RA, La Mendola C, Scotet E, Dieli F, Salerno A (2006) CXCR5 identifies a subset of Vγ9Vδ2 T cells which secrete IL-4 and IL-10 and help B cells for antibody production. J Immunol 177(8):5290–5295. https://doi.org/10.4049/jimmunol.177.8.5290

    Article  CAS  PubMed  Google Scholar 

  43. McCarthy NE, Eberl M (2018) Human γδ T-cell control of mucosal immunity and inflammation. Front Immunol 9:985–985. https://doi.org/10.3389/fimmu.2018.00985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cook L, Miyahara N, Jin N, Wands JM, Taube C, Roark CL, Potter TA, Gelfand EW, O’Brien RL, Born WK (2008) Evidence that CD8+ dendritic cells enable the development of gammadelta T cells that modulate airway hyperresponsiveness. J Immunol 181(1):309–319

    Article  CAS  Google Scholar 

  45. Papotto PH, Gonçalves-Sousa N, Schmolka N, Iseppon A, Mensurado S, Stockinger B, Ribot JC, Silva-Santos B (2017) IL-23 drives differentiation of peripheral γδ17 T cells from adult bone marrow-derived precursors. EMBO Rep e201744200. https://doi.org/10.15252/embr.201744200

    Article  CAS  Google Scholar 

  46. Liang D, Zuo A, Shao H, Born WK, O'Brien RL, Kaplan HJ, Sun D (2013) IL-23 receptor expression on γδ T cells correlates with their enhancing or suppressive effects on autoreactive T cells in experimental autoimmune uveitis. J Immunol 191(3):1118–1125. https://doi.org/10.4049/jimmunol.1300626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Roark CL, French JD, Taylor MA, Bendele AM, Born WK, O'Brien RL (2007) Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing gamma delta T cells. J Immunol 179(8):5576–5583

    Article  CAS  Google Scholar 

  48. Ramírez-Valle F, Gray EE, Cyster JG (2015) Inflammation induces dermal Vγ4+ γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17-driven responses. Proc Natl Acad Sci U S A 112(26):8046–8051. https://doi.org/10.1073/pnas.1508990112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Adamopoulos IE, Suzuki E, Chao C-C, Gorman D, Adda S, Maverakis E, Zarbalis K, Geissler R, Asio A, Blumenschein WM, McClanahan T, De Waal MR, Gershwin ME, Bowman EP (2015) IL-17A gene transfer induces bone loss and epidermal hyperplasia associated with psoriatic arthritis. Ann Rheum Dis 74(6):1284–1292. https://doi.org/10.1136/annrheumdis-2013-204782

    Article  CAS  PubMed  Google Scholar 

  50. Suzuki E, Maverakis E, Sarin R, Bouchareychas L, Kuchroo VK, Nestle FO, Adamopoulos IE (2016) T cell-independent mechanisms associated with neutrophil extracellular trap formation and selective autophagy in IL-17A-mediated epidermal hyperplasia. J Immunol 197(11):4403–4412. https://doi.org/10.4049/jimmunol.1600383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KHG (2009) Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 31(2):331–341. https://doi.org/10.1016/j.immuni.2009.08.001

    Article  CAS  PubMed  Google Scholar 

  52. Turchinovich G, Hayday Adrian C (2011) Skint-1 identifies a common molecular mechanism for the development of interferon-γ-secreting versus interleukin-17-secreting γδ T cells. Immunity 35(1):59–68. https://doi.org/10.1016/j.immuni.2011.04.018

    Article  CAS  PubMed  Google Scholar 

  53. Heilig JS, Tonegawa S (1986) Diversity of murine gamma genes and expression in fetal and adult T lymphocytes. Nature 322(6082):836–840. https://doi.org/10.1038/322836a0

    Article  CAS  PubMed  Google Scholar 

  54. Dillen CA, Pinsker BL, Marusina AI, Merleev AA, Farber ON, Liu H, Archer NK, Lee DB, Wang Y, Ortines RV, Lee SK, Marchitto MC, Cai SS, Ashbaugh AG, May LS, Holland SM, Freeman AF, Miller LG, Yeaman MR, Simon SI, Milner JD, Maverakis E, Miller LS (2018) Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection. J Clin Invest 128(3):1026–1042. https://doi.org/10.1172/JCI96481

    Article  PubMed  PubMed Central  Google Scholar 

  55. 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 Genet 40(5):656–662. https://doi.org/10.1038/ng.108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chodaczek G, Papanna V, Zal MA, Zal T (2012) Body-barrier surveillance by epidermal γδ TCRs. Nat Immunol 13(3):272–282. https://doi.org/10.1038/ni.2240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mair F, Joller S, Hoeppli R, Onder L, Hahn M, Ludewig B, Waisman A, Becher B (2015) The NFκB-inducing kinase is essential for the developmental programming of skin-resident and IL-17-producing γδ T cells. eLife 4:e10087. https://doi.org/10.7554/eLife.10087

    Article  PubMed  PubMed Central  Google Scholar 

  58. Itohara S, Farr AG, Lafaille JJ, Bonneville M, Takagaki Y, Haas W, Tonegawa S (1990) Homing of a γδ thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature 343:754. https://doi.org/10.1038/343754a0

    Article  CAS  Google Scholar 

  59. Roark CL, Aydintug MK, Lewis J, Yin X, Lahn M, Hahn Y-S, Born WK, Tigelaar RE, O’Brien RL (2004) Subset-specific, uniform activation among Vγ6/Vδ1+ γδ T cells elicited by inflammation. J Leukoc Biol 75(1):68–75. https://doi.org/10.1189/jlb.0703326

    Article  CAS  PubMed  Google Scholar 

  60. Hayes SM, Sirr A, Jacob S, Sim GK, Augustin A (1996) Role of IL-7 in the shaping of the pulmonary gamma delta T cell repertoire. J Immunol 156(8):2723–2729

    CAS  PubMed  Google Scholar 

  61. Mamedov MR, Scholzen A, Nair RV, Cumnock K, Kenkel JA, Oliveira JHM, Trujillo DL, Saligrama N, Zhang Y, Rubelt F, Schneider DS, Chien Y-h, Sauerwein RW, Davis MM (2018) A macrophage colony-stimulating-factor-producing γδ T cell subset prevents malarial parasitemic recurrence. Immunity 48(2):350–363.e357. https://doi.org/10.1016/j.immuni.2018.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hartl D, Krauss-Etschmann S, Koller B, Hordijk PL, Kuijpers TW, Hoffmann F, Hector A, Eber E, Marcos V, Bittmann I, Eickelberg O, Griese M, Roos D (2008) Infiltrated neutrophils acquire novel chemokine receptor expression and chemokine responsiveness in chronic inflammatory lung diseases. J Immunol 181(11):8053–8067. https://doi.org/10.4049/jimmunol.181.11.8053

    Article  CAS  PubMed  Google Scholar 

  63. Jennifer MR, Sivasami P, Harshini KA, Jerry WR, Timothy AS, Jerry RM, Montelongo M, Vincent TC, Teluguakula N (2019) Neutrophils induce a novel chemokine receptors repertoire during influenza pneumonia. Front Cell Infect Microbiol In Press

  64. Jiang X, Park CO, Geddes Sweeney J, Yoo MJ, Gaide O, Kupper TS (2017) Dermal γδ T cells do not freely re-circulate out of skin and produce IL-17 to promote neutrophil infiltration during primary contact hypersensitivity. PLoS One 12(1):e0169397. https://doi.org/10.1371/journal.pone.0169397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bouchareychas L, Grössinger EM, Kang M, Adamopoulos IE (2018) γδTCR regulates production of interleukin-27 by neutrophils and attenuates inflammatory arthritis. Sci Rep 8(1):7590–7590. https://doi.org/10.1038/s41598-018-25988-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rani M, Zhang Q, Schwacha MG (2014) Gamma delta (γδ) T-cells regulate wound myeloid cell activity after burn. Shock 42(2):133–141. https://doi.org/10.1097/SHK.0000000000000176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mokuno Y, Matsuguchi T, Takano M, Nishimura H, Washizu J, Ogawa T, Takeuchi O, Akira S, Nimura Y, Yoshikai Y (2000) Expression of toll-like receptor 2 on gamma delta T cells bearing invariant V gamma 6/V delta 1 induced by Escherichia coli infection in mice. J Immunol 165(2):931–940. https://doi.org/10.4049/jimmunol.165.2.931

    Article  CAS  PubMed  Google Scholar 

  68. Cheng L, Cui Y, Shao H, Han G, Zhu L, Huang Y, O'Brien RL, Born WK, Kaplan HJ, Sun D (2008) Mouse gammadelta T cells are capable of expressing MHC class II molecules, and of functioning as antigen-presenting cells. J Neuroimmunol 203(1):3–11. https://doi.org/10.1016/j.jneuroim.2008.06.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lanier LL, Sun JC (2009) Do the terms innate and adaptive immunity create conceptual barriers? Nat Rev Immunol 9(5):302–303. https://doi.org/10.1038/nri2547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 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(4):667–674. https://doi.org/10.1016/0092-8674(89)90135-9

    Article  CAS  PubMed  Google Scholar 

  71. Lalor SJ, McLoughlin RM (2016) Memory γδ T cells–newly appreciated protagonists in infection and immunity. Trends Immunol 37(10):690–702. https://doi.org/10.1016/j.it.2016.07.006

    Article  CAS  PubMed  Google Scholar 

  72. Hartwig T, Pantelyushin S, Croxford AL, Kulig P, Becher B (2015) Dermal IL-17-producing γδ T cells establish long-lived memory in the skin. Eur J Immunol 45(11):3022–3033. https://doi.org/10.1002/eji.201545883

    Article  CAS  PubMed  Google Scholar 

  73. Huang Y, Heiser RA, Detanico TO, Getahun A, Kirchenbaum GA, Casper TL, Aydintug MK, Carding SR, Ikuta K, Huang H, Cambier JC, Wysocki LJ, O'Brien RL, Born WK (2015) γδ T cells affect IL-4 production and B-cell tolerance. Proc Natl Acad Sci U S A 112(1):E39–E48. https://doi.org/10.1073/pnas.1415107111

    Article  CAS  PubMed  Google Scholar 

  74. Crawford G, Hayes MD, Seoane RC, Ward S, Dalessandri T, Lai C, Healy E, Kipling D, Proby C, Moyes C, Green K, Best K, Haniffa M, Botto M, Dunn-Walters D, Strid J (2018) Epithelial damage and tissue γδ T cells promote a unique tumor-protective IgE response. Nat Immunol 19(8):859–870. https://doi.org/10.1038/s41590-018-0161-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Rezende RM, Lanser AJ, Rubino S, Kuhn C, Skillin N, Moreira TG, Liu S, Gabriely G, David BA, Menezes GB, Weiner HL (2018) γδ T cells control humoral immune response by inducing T follicular helper cell differentiation. Nat Commun 9(1):3151–3151. https://doi.org/10.1038/s41467-018-05487-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. J-s D, Visperas A, Dong C, Baldwin WM 3rd, Min B (2011) Cutting edge: Generation of colitogenic Th17 CD4 T cells is enhanced by IL-17+ γδ T cells. J Immunol 186(8):4546–4550. https://doi.org/10.4049/jimmunol.1004021

    Article  CAS  Google Scholar 

  77. Cui Y, Shao H, Lan C, Nian H, O'Brien RL, Born WK, Kaplan HJ, Sun D (2009) Major role of gamma delta T cells in the generation of IL-17+ uveitogenic T cells. J Immunol 183(1):560–567. https://doi.org/10.4049/jimmunol.0900241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KHG (2009) Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. Immunity 31(2):331–341. https://doi.org/10.1016/j.immuni.2009.08.001

    Article  CAS  PubMed  Google Scholar 

  79. Hahn Y-S, Taube C, Jin N, Sharp L, Wands JM, Aydintug MK, Lahn M, Huber SA, O’Brien RL, Gelfand EW, Born WK (2004) Different potentials of gamma delta T cell subsets in regulating airway responsiveness: V gamma 1+ cells, but not V gamma 4+ cells, promote airway hyperreactivity, Th2 cytokines, and airway inflammation. J Immunol 172(5):2894–2902. https://doi.org/10.4049/jimmunol.172.5.2894

    Article  CAS  PubMed  Google Scholar 

  80. Park S-G, Mathur R, Long M, Hosh N, Hao L, Hayden MS, Ghosh S (2010) T regulatory cells maintain intestinal homeostasis by suppressing γδ T cells. Immunity 33(5):791–803. https://doi.org/10.1016/j.immuni.2010.10.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Imai Y, Ayithan N, Wu X, Yuan Y, Wang L, Hwang ST (2015) Cutting edge: PD-1 regulates imiquimod-induced psoriasiform dermatitis through inhibition of IL-17A expression by innate γδ-low T cells. J Immunol 195(2):421–425. https://doi.org/10.4049/jimmunol.1500448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Jameson J, Ugarte K, Chen N, Yachi P, Fuchs E, Boismenu R, Havran WL (2002) A role for skin γδ T cells in wound repair. Science 296(5568):747–749. https://doi.org/10.1126/science.1069639

    Article  CAS  PubMed  Google Scholar 

  83. Akitsu A, Ishigame H, Kakuta S, Chung S-H, Ikeda S, Shimizu K, Kubo S, Liu Y, Umemura M, Matsuzaki G, Yoshikai Y, Saijo S, Iwakura Y (2015) IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2(+)Vγ6(+)γδ T cells. Nat Commun 6:7464–7464. https://doi.org/10.1038/ncomms8464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kulig P, Musiol S, Freiberger SN, Schreiner B, Gyülveszi G, Russo G, Pantelyushin S, Kishihara K, Alessandrini F, Kündig T, Sallusto F, Hofbauer GFL, Haak S, Becher B (2016) IL-12 protects from psoriasiform skin inflammation. Nat Commun 7:13466–13466. https://doi.org/10.1038/ncomms13466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Simonian PL, Roark CL, Diaz del Valle F, Palmer BE, Douglas IS, Ikuta K, Born WK, O’Brien RL, Fontenot AP (2006) Regulatory role of γδ T cells in the recruitment of CD4+ and CD8+ T cells to lung and subsequent pulmonary fibrosis. J Immunol 177(7):4436–4443. https://doi.org/10.4049/jimmunol.177.7.4436

    Article  CAS  PubMed  Google Scholar 

  86. Laggner U, Di Meglio P, Perera GK, Hundhausen C, Lacy KE, Ali N, Smith CH, Hayday AC, Nickoloff BJ, Nestle FO (2011) Identification of a novel proinflammatory human skin-homing Vγ9Vδ2 T cell subset with a potential role in psoriasis. J Immunol 187(5):2783–2793. https://doi.org/10.4049/jimmunol.1100804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Cibrian D, Saiz ML, de la Fuente H, Sánchez-Díaz R, Moreno-Gonzalo O, Jorge I, Ferrarini A, Vázquez J, Punzón C, Fresno M, Vicente-Manzanares M, Daudén E, Fernández-Salguero PM, Martín P, Sánchez-Madrid F (2016) CD69 controls the uptake of L-tryptophan through LAT1-CD98 and AhR-dependent secretion of IL-22 in psoriasis. Nat Immunol 17(8):985–996. https://doi.org/10.1038/ni.3504

    Article  CAS  PubMed  Google Scholar 

  88. Brennan FM, Londei M, Jackson AM, Hercend T, Brenner MB, Maini RN, Feldmann M (1988) T cells expressing γδ chain receptors in rheumatoid arthritis. J Autoimmun 1(4):319–326. https://doi.org/10.1016/0896-8411(88)90002-9

    Article  CAS  PubMed  Google Scholar 

  89. Mo W-X, Yin S-S, Chen H, Zhou C, Zhou J-X, Zhao L-D, Fei Y-Y, Yang H-X, Guo J-B, Mao Y-J, Huang L-F, Zheng W-J, Zhang W, Zhang J-M, He W, Zhang X (2017) Chemotaxis of Vδ2 T cells to the joints contributes to the pathogenesis of rheumatoid arthritis. Ann Rheum Dis 76(12):2075–2084. https://doi.org/10.1136/annrheumdis-2016-211069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Keystone EC, Rittershaus C, Wood N, Snow KM, Flatow J, Purvis JC, Poplonski L, Kung PC (1991) Elevation of a gamma delta T cell subset in peripheral blood and synovial fluid of patients with rheumatoid arthritis. Clin Exp Immunol 84(1):78–82

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Bendersky A, Marcu-Malina V, Berkun Y, Gerstein M, Nagar M, Goldstein I, Padeh S, Bank I (2012) Cellular interactions of synovial fluid γδ T cells in juvenile idiopathic arthritis. J Immunol 188(9):4349–4359. https://doi.org/10.4049/jimmunol.1102403

    Article  CAS  PubMed  Google Scholar 

  92. Blazek K, Eames HL, Weiss M, Byrne AJ, Perocheau D, Pease JE, Doyle S, McCann F, Williams RO, Udalova IA (2015) IFN-λ resolves inflammation via suppression of neutrophil infiltration and IL-1β production. J Exp Med 212(6):845–853. https://doi.org/10.1084/jem.20140995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, Martin TJ, Suda T (1999) IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103(9):1345–1352. https://doi.org/10.1172/JCI5703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Adamopoulos IE, Chao C-C, Geissler R, Laface D, Blumenschein W, Iwakura Y, McClanahan T, Bowman EP (2010) Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors. Arthritis Res Ther 12(1):R29–R29. https://doi.org/10.1186/ar2936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Osta B, Roux J-P, Lavocat F, Pierre M, Ndongo-Thiam N, Boivin G, Miossec P (2015) Differential effects of IL-17A and TNF-α on osteoblastic differentiation of isolated synoviocytes and on bone explants from arthritis patients. Front Immunol 6:151–151. https://doi.org/10.3389/fimmu.2015.00151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Jo S, Wang SE, Lee YL, Kang S, Lee B, Han J, Sung I-H, Park Y-S, Bae S-C, Kim T-H (2018) IL-17A induces osteoblast differentiation by activating JAK2/STAT3 in ankylosing spondylitis. Arthritis Res Ther 20(1):115–115. https://doi.org/10.1186/s13075-018-1582-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. van Tok MN, van Duivenvoorde LM, Kramer I, Ingold P, Pfister S, Roth L, Blijdorp IC, van de Sande MGH, Taurog JD, Kolbinger F, Baeten DL (2019) Interleukin-17A inhibition diminishes inflammation and new bone formation in experimental spondyloarthritis. Arthritis Rheum 71(4):612–625. https://doi.org/10.1002/art.40770

    Article  CAS  Google Scholar 

  98. Ono T, Okamoto K, Nakashima T, Nitta T, Hori S, Iwakura Y, Takayanagi H (2016) IL-17-producing γδ T cells enhance bone regeneration. Nat Commun 7:10928. https://doi.org/10.1038/ncomms10928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Phalke SP, Chiplunkar SV (2015) Activation status of γδ T cells dictates their effect on osteoclast generation and bone resorption. Bone Rep 3:95–103. https://doi.org/10.1016/j.bonr.2015.10.004

    Article  PubMed  PubMed Central  Google Scholar 

  100. Zhu X, Zeng Z, Qiu D, Chen J (2018) Vγ9Vδ2 T cells inhibit immature dendritic cell transdifferentiation into osteoclasts through downregulation of RANK, c-Fos and ATP6V0D2. Int J Mol Med 42(4):2071–2079. https://doi.org/10.3892/ijmm.2018.3791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gray EE, Suzuki K, Cyster JG (2011) Cutting edge: identification of a motile IL-17-producing gammadelta T cell population in the dermis. J Immunol 186(11):6091–6095. https://doi.org/10.4049/jimmunol.1100427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Dalessandri T, Crawford G, Hayes M, Castro Seoane R, Strid J (2016) IL-13 from intraepithelial lymphocytes regulates tissue homeostasis and protects against carcinogenesis in the skin. Nat Commun 7:12080–12080. https://doi.org/10.1038/ncomms12080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gray EE, Ramírez-Valle F, Xu Y, Wu S, Wu Z, Karjalainen KE, Cyster JG (2013) Deficiency in IL-17-committed Vγ4(+) γδ T cells in a spontaneous Sox13-mutant CD45.1(+) congenic mouse substrain provides protection from dermatitis. Nat Immunol 14(6):584–592

    Article  CAS  Google Scholar 

  104. Shibata S, Tada Y, Hau CS, Mitsui A, Kamata M, Asano Y, Sugaya M, Kadono T, Masamoto Y, Kurokawa M, Yamauchi T, Kubota N, Kadowaki T, Sato S (2015) Adiponectin regulates psoriasiform skin inflammation by suppressing IL-17 production from γδ-T cells. Nat Commun 6:7687. https://doi.org/10.1038/ncomms8687

    Article  CAS  PubMed  Google Scholar 

  105. Reinhardt A, Yevsa T, Worbs T, Lienenklaus S, Sandrock I, Oberdörfer L, Korn T, Weiss S, Förster R, Prinz I (2016) Interleukin-23–dependent γ/δ T cells produce interleukin-17 and accumulate in the enthesis, aortic valve, and ciliary body in mice. Arthritis Rheum 68(10):2476–2486. https://doi.org/10.1002/art.39732

    Article  CAS  Google Scholar 

  106. Corthay A, Hansson A-S, Holmdahl R (2000) T lymphocytes are not required for the spontaneous development of entheseal ossification leading to marginal ankylosis in the DBA/1 mouse. Arthritis Rheum 43(4):844–851. https://doi.org/10.1002/1529-0131(200004)43:4<844::aid-anr15>3.0.co;2-b

    Article  CAS  PubMed  Google Scholar 

  107. Cuthbert RJ, Fragkakis EM, Dunsmuir R, Li Z, Coles M, Marzo-Ortega H, Giannoudis PV, Jones E, El-Sherbiny YM, McGonagle D (2017) Brief Report: Group 3 innate lymphoid cells in human enthesis. Arthritis Rheum 69(9):1816–1822. https://doi.org/10.1002/art.40150

    Article  CAS  Google Scholar 

  108. Reinhardt A, Prinz I (2018) Whodunit? The contribution of interleukin (IL)-17/IL-22-producing γδ T cells, αβ T cells, and innate lymphoid cells to the pathogenesis of spondyloarthritis. Front Immunol 9:885–885. https://doi.org/10.3389/fimmu.2018.00885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Merleev AA, Marusina AI, Ma C, Elder JT, Tsoi LC, Raychaudhuri SP, Weidinger S, Wang EA, Adamopoulos IE, Luxardi G, Gudjonsson JE, Shimoda M, Maverakis E (2018) Meta-analysis of RNA sequencing datasets reveals an association between TRAJ23, psoriasis, and IL-17A. JCI Insight 3(13):e120682. https://doi.org/10.1172/jci.insight.120682

    Article  PubMed Central  Google Scholar 

  110. Cai Y, Fleming C, Yan J (2013) Dermal γδ T cells — a new player in the pathogenesis of psoriasis. Int Immunopharmacol 16(3):388–391. https://doi.org/10.1016/j.intimp.2013.02.018

    Article  CAS  PubMed  Google Scholar 

  111. Man F, Lim L, Volpe A, Gabizon A, Shmeeda H, Draper B, Parente-Pereira AC, Maher J, Blower PJ, Fruhwirth GO, T. M. de Rosales R (2019) In vivo PET tracking of 89Zr-labeled Vγ9Vδ2 T cells to mouse xenograft breast tumors activated with liposomal alendronate. Mol Ther 27(1):219–229. https://doi.org/10.1016/j.ymthe.2018.10.006

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant R01AR062173, and a National Psoriasis Foundation Translational Research grant to IEA. EM was supported by (1DP2OD008752).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA

    Cuong Thach Nguyen & Iannis E. Adamopoulos

  2. NTT Hi-Tech Institute, Nguyen Tat Thanh University, Ho Chi Minh City, Vietnam

    Cuong Thach Nguyen

  3. Department of Dermatology, School of Medicine, University of California at Davis, Davis, CA, USA

    Emanual Maverakis

  4. Division of Infection and Immunity, School of Medicine and Systems Immunity Research Institute, Cardiff University, Cardiff, CF14 4XN, UK

    Matthias Eberl

  5. Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, CA, USA

    Iannis E. Adamopoulos

Authors
  1. Cuong Thach Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emanual Maverakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthias Eberl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Iannis E. Adamopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Iannis E. Adamopoulos.

Ethics declarations

Conflict of interest

IEA has received grants, salary, consulting fees from Schering Plough Biopharma/Merck, Novartis, Pfizer and Tanabe Research Labs USA. The authors have no other conflicts of interest to declare.

Additional information

This article is a contribution to the special issue on Osteoimmunology - Guest Editor: Mary Nakamura

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nguyen, C.T., Maverakis, E., Eberl, M. et al. γδ T cells in rheumatic diseases: from fundamental mechanisms to autoimmunity. Semin Immunopathol 41, 595–605 (2019). https://doi.org/10.1007/s00281-019-00752-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-019-00752-5

Keywords

Search

Navigation