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

  • Cuong Thach Nguyen
  • Emanual Maverakis
  • Matthias Eberl
  • Iannis E. AdamopoulosEmail author
Review

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.

Keywords

γδ T cells T cell receptor (TCR) Bone remodeling Autoimmune diseases Skin and joint inflammation Psoriatic arthritis 

Notes

Funding information

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).

Compliance with ethical standards

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.

References

  1. 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 CrossRefGoogle Scholar
  2. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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 CrossRefPubMedGoogle Scholar
  4. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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 CrossRefPubMedGoogle Scholar
  6. 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 CrossRefPubMedGoogle Scholar
  7. 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 CrossRefPubMedGoogle Scholar
  8. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 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 CrossRefPubMedGoogle Scholar
  11. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 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 CrossRefPubMedGoogle Scholar
  13. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 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 CrossRefPubMedGoogle Scholar
  16. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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):491–505CrossRefPubMedGoogle Scholar
  19. 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):1067–1075CrossRefPubMedGoogle Scholar
  20. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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 CrossRefPubMedGoogle Scholar
  23. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 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 CrossRefPubMedGoogle Scholar
  28. 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 CrossRefPubMedGoogle Scholar
  29. 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 CrossRefPubMedGoogle Scholar
  30. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 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 CrossRefPubMedGoogle Scholar
  32. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 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 CrossRefPubMedGoogle Scholar
  34. 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 CrossRefPubMedGoogle Scholar
  35. 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 CrossRefGoogle Scholar
  36. 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 CrossRefPubMedGoogle Scholar
  37. 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):1239–1244CrossRefPubMedGoogle Scholar
  38. 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 CrossRefPubMedGoogle Scholar
  39. 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 CrossRefPubMedGoogle Scholar
  40. 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):4304–4314CrossRefPubMedPubMedCentralGoogle Scholar
  41. 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
  42. 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 CrossRefPubMedGoogle Scholar
  43. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 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):309–319CrossRefPubMedPubMedCentralGoogle Scholar
  45. 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
  46. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 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):5576–5583CrossRefPubMedPubMedCentralGoogle Scholar
  48. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 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 CrossRefPubMedGoogle Scholar
  50. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 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 CrossRefPubMedGoogle Scholar
  52. 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 CrossRefPubMedGoogle Scholar
  53. 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 CrossRefPubMedGoogle Scholar
  54. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 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 CrossRefPubMedGoogle Scholar
  59. 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 CrossRefPubMedGoogle Scholar
  60. 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):2723–2729PubMedGoogle Scholar
  61. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 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 CrossRefPubMedGoogle Scholar
  63. 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 PressGoogle Scholar
  64. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  65. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  66. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 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 CrossRefPubMedGoogle Scholar
  68. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  69. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  70. 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 CrossRefPubMedGoogle Scholar
  71. 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 CrossRefPubMedGoogle Scholar
  72. 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 CrossRefPubMedGoogle Scholar
  73. 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 CrossRefPubMedGoogle Scholar
  74. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  75. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  76. 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 CrossRefGoogle Scholar
  77. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  78. 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 CrossRefPubMedGoogle Scholar
  79. 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 CrossRefPubMedGoogle Scholar
  80. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  81. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  82. 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 CrossRefPubMedGoogle Scholar
  83. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  84. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  85. 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 CrossRefPubMedGoogle Scholar
  86. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  87. 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 CrossRefPubMedGoogle Scholar
  88. 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 CrossRefPubMedGoogle Scholar
  89. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  90. 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):78–82PubMedPubMedCentralGoogle Scholar
  91. 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 CrossRefPubMedGoogle Scholar
  92. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  93. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  94. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  95. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  96. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  97. 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 CrossRefGoogle Scholar
  98. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  99. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  100. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  101. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  102. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  103. 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):584–592CrossRefPubMedPubMedCentralGoogle Scholar
  104. 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 CrossRefPubMedGoogle Scholar
  105. 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 CrossRefGoogle Scholar
  106. 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 CrossRefPubMedGoogle Scholar
  107. 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 CrossRefGoogle Scholar
  108. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  109. 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 CrossRefPubMedCentralGoogle Scholar
  110. 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 CrossRefPubMedGoogle Scholar
  111. 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 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Cuong Thach Nguyen
    • 1
    • 2
  • Emanual Maverakis
    • 3
  • Matthias Eberl
    • 4
  • Iannis E. Adamopoulos
    • 1
    • 5
    Email author
  1. 1.Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of CaliforniaDavisUSA
  2. 2.NTT Hi-Tech InstituteNguyen Tat Thanh UniversityHo Chi Minh CityVietnam
  3. 3.Department of Dermatology, School of MedicineUniversity of California at DavisDavisUSA
  4. 4.Division of Infection and Immunity, School of Medicine and Systems Immunity Research InstituteCardiff UniversityCardiffUK
  5. 5.Institute for Pediatric Regenerative MedicineShriners Hospitals for Children Northern CaliforniaSacramentoUSA

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