Review Article | Published:

When worlds collide: Th17 and Treg cells in cancer and autoimmunity

Cellular & Molecular Immunologyvolume 15pages458469 (2018) | Download Citation



The balance between Th17 cells and regulatory T cells (Tregs) has emerged as a prominent factor in regulating autoimmunity and cancer. Th17 cells are vital for host defense against pathogens but have also been implicated in causing autoimmune disorders and cancer, though their role in carcinogenesis is less well understood. Tregs are required for self-tolerance and defense against autoimmunity and often correlate with cancer progression. This review addresses the importance of a functional homeostasis between these two subsets in health and the consequences of its disruption when these forces collide in disease. Importantly, we discuss the ability of Th17 cells to mediate cancer regression in immunotherapy, including adoptive transfer and checkpoint blockade therapy, and the therapeutic possibilities of purposefully offsetting the Th17/Treg balance to treat patients with cancer as well as those with autoimmune diseases.

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  1. 1.

    Tada, T., Takemori, T., Okumura, K., Nonaka, M. & Tokuhisa, T. Two distinct types of helper T cells involved in the secondary antibody response: independent and synergistic effects of Ia- and Ia+ helper T cells. J. Exp. Med. 147, 446–458 (1978).

  2. 2.

    Zhu, J., Yamane, H. & Paul, W. E. Differentiation of effector CD4 T cell populations (*). Annu. Rev. Immunol. 28, 445–489 (2010).

  3. 3.

    Luckheeram, R. V., Zhou, R., Verma, A. D. & Xia, B. CD4(+)T cells: differentiation and functions. Clin. Dev. Immunol. 2012, 925135 (2012).

  4. 4.

    Szabo, S. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655–669 (2000).

  5. 5.

    Zheng, W. & Flavell, R. The transcription factor GATA3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).

  6. 6.

    Reiner, S. L. Development in motion: helper T cells at work. Cell 129, 33–36 (2007).

  7. 7.

    Ivanov, I. I. et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+T helper cells. Cell 126, 1121–1133 (2006).

  8. 8.

    Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).

  9. 9.

    Chang, S. H. & Dong, C. A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell. Res. 17, 435–440 (2007).

  10. 10.

    Dong, C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat. Rev. Immunol. 8, 337–348 (2008).

  11. 11.

    Noack, M. & Miossec, P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun. Rev. 13, 668–677 (2014).

  12. 12.

    Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191–197 (2007).

  13. 13.

    Adeegbe, D., Bayer, A. L., Levy, R. B. & Malek, T. R. Cutting edge: allogeneic CD4+CD25+Foxp3+T regulatory cells suppress autoimmunity while establishing transplantation tolerance. J. Immunol. 176, 7149–7153 (2006).

  14. 14.

    Dardalhon, V. et al. IL-4 inhibits TGF-beta-induced Foxp3+T cells and, together with TGF-beta, generates IL-9+IL-10+Foxp3(-) effector T cells. Nat. Immunol. 9, 1347–1355 (2008).

  15. 15.

    Veldhoen, M. et al. Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 9, 1341–1346 (2008).

  16. 16.

    Schmitt, E. et al. IL-9 production of naive CD4+T cells depends on IL-2, is synergistically enhanced by a combination of TGF-B and IL-4, and is inhibited by IFN-y. J. Immunol. 153, 3989–3996 (1994).

  17. 17.

    Gerlach, K. et al. TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat. Immunol. 15, 676–686 (2014).

  18. 18.

    Staudt, V. et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33, 192–202 (2010).

  19. 19.

    Jabeen, R. et al. Th9 cell development requires a BATF-regulated transcriptional network. J. Clin. Invest. 123, 4641–4653 (2013).

  20. 20.

    Malik, S. et al. Transcription factor Foxo1 is essential for IL-9 induction in T helper cells. Nat. Commun. 8, 815 (2017).

  21. 21.

    Nowak, E. C. et al. IL-9 as a mediator of Th17-driven inflammatory disease. J. Exp. Med. 206, 1653–1660 (2009).

  22. 22.

    Townsend, M. et al. IL-9 deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity 13, 573–583 (2000).

  23. 23.

    Elyaman, W. et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+natural regulatory T cells. Proc. Natl Acad. Sci. USA 106, 12885–12890 (2009).

  24. 24.

    Vegran, F. et al. The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells. Nat. Immunol. 15, 758–766 (2014).

  25. 25.

    Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A. & Sallusto, F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat. Immunol. 10, 857–863 (2009).

  26. 26.

    Cai, Y., Fleming, C. & Yan, J. New insights of T cells in the pathogenesis of psoriasis. Cell Mol. Immunol. 9, 302–309 (2012).

  27. 27.

    Eyerich, S. et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J. Clin. Invest. 119, 3573–3585 (2009).

  28. 28.

    Trifari, S., Kaplan, C. D., Tran, E. H., Crellin, N. K. & Spits, H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat. Immunol. 10, 864–871 (2009).

  29. 29.

    Honda, K. IL-22 from T cells: better late than never. Immunity 37, 952–954 (2012).

  30. 30.

    Basu, R. et al. Th22 cells are an important source of IL-22 for host protectioni against enteropathogenic bacteria. Immunity 37, 1061–1075 (2012).

  31. 31.

    Crotty, S. T follicular helper cell differentiation, function, and roles in disease. Immunity 41, 529–542 (2014).

  32. 32.

    Wang, Y. et al. Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells. Nat. Immunol. 18, 921–930 (2017).

  33. 33.

    Weinstein J. S. et al. STAT4 and T-bet control follicular helper T cell development in viral infections. J Exp Med. 215, 337–355 (2017).

  34. 34.

    Andris, F. et al. The transcription factor c-Maf promotes the differentiation of follicular helper T cells. Front. Immunol. 8, 480 (2017).

  35. 35.

    Bollig, N. et al. Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation. Proc. Natl Acad. Sci. USA 109, 8664–8669 (2012).

  36. 36.

    Ise, W. et al. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat. Immunol. 12, 536–543 (2011).

  37. 37.

    Coffman, R. Origins of the Th1-Th2 model: a personal perspective. Nat. Immunol. 7, 539–541 (2006).

  38. 38.

    Weaver, C. T., Harrington, L. E., Mangan, P. R., Gavrieli, M. & Murphy, K. M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).

  39. 39.

    Mossman, T., Cherwinski, H., Bond, M., Giedlin, M. & Coffman, R. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2357 (1986).

  40. 40.

    Steinman, L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat. Med. 13, 139–145 (2007).

  41. 41.

    Billiau, A. et al. Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma. J. Immunol. 140, 1506–1510 (1988).

  42. 42.

    Voorthuis, J. et al. Suppression of experimental allergic encephalomyelitis by intraventricular administration of interferon-gamma in Lewis rats. Clin. Exp. Immunol. 81, 183–188 (1990).

  43. 43.

    Willenborg, D., Fordhan, S., Bernard, C., Cowden, W. & Ramshaw, I. IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J. Immunol. 157, 3223–3227 (1996).

  44. 44.

    Krakowski, M. & Owens, T. Interferon-y confers resistance to experimental allergic encephalomyelitis. Eur. J. Immunol. 26, 1641–1646 (1996).

  45. 45.

    Ferber, I. et al. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalitis (EAE). J. Immunol. 156, 5–7 (1996).

  46. 46.

    Cruz, A. et al. Cutting Edge: IFN- Regulates the Induction and Expansion of IL-17-Producing CD4 T Cells during Mycobacterial Infection. J. Immunol. 177, 1416–1420 (2006).

  47. 47.

    Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).

  48. 48.

    Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

  49. 49.

    Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

  50. 50.

    Tato, C. & O’Shea, J. J. What does it mean to be just 17? Nature 441, 166–168 (2006).

  51. 51.

    Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 42, 744–748 (2003).

  52. 52.

    Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

  53. 53.

    Harrington, L. E. et al. Interleukin 17-producing CD4+effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).

  54. 54.

    Stritesky, G. L., Yeh, N. & Kaplan, M. H. IL-23 promotes maintenance but not commitment to the Th17 lineage. J. Immunol. 181, 5948–5955 (2008).

  55. 55.

    Mailer, R. K. et al. IL-1beta promotes Th17 differentiation by inducing alternative splicing of FOXP3. Sci. Rep. 5, 14674 (2015).

  56. 56.

    Zhang, S. et al. Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation. Nature 551, 105–109 (2017).

  57. 57.

    Qin, H. et al. TGF-beta promotes Th17 cell development through inhibition of SOCS3. J. Immunol. 183, 97–105 (2009).

  58. 58.

    Kim, H. S. et al. PTEN drives Th17 cell differentiation by preventing IL-2 production. J. Exp. Med. 214, 3381–3398 (2017).

  59. 59.

    Yang, X. O. et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem. 282, 9358–9363 (2007).

  60. 60.

    O’Shea, J. J. & Paul, W. E. Mechanisms underlying lineage commitment and plasticity of helper CD4+T cells. Science 327, 1098–1102 (2010).

  61. 61.

    McGeachy, M. J. et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat. Immunol. 8, 1390–1397 (2007).

  62. 62.

    McGeachy, M. J. et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat. Immunol. 10, 314–324 (2009).

  63. 63.

    Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448, 484–487 (2007).

  64. 64.

    Carr, T. M., Wheaton, J. D., Houtz, G. M. & Ciofani, M. JunB promotes Th17 cell identity and restrains alternative CD4(+) T-cell programs during inflammation. Nat. Commun. 8, 301 (2017).

  65. 65.

    Khader, S. A., Gaffen, S. L. & Kolls, J. K. Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol. 2, 403–411 (2009).

  66. 66.

    Kinugasa, T., Sakaguchi, T., Gu, X. & Reinecker, H. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 118, 1001–1011 (2000).

  67. 67.

    Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and Th17 Cells. Annu. Rev. Immunol. 27, 485–517 (2009).

  68. 68.

    Fossiez, F. et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Ex. Med. 183, 2593–2603 (1996).

  69. 69.

    Ye, P. et al. Requirement of Interleukin 17 receptor signalling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 194, 519–527 (2001).

  70. 70.

    Laan, M. et al. Neutrophil recruitment by human IL-17 via CXC chemokine release in the airways. J. Immunol. 162, 2347–2352 (1999).

  71. 71.

    Tan, W., Huang, W., Zhong, Q. & Schwarzenberger, P. IL-17 receptor knockout mice have enhanced myelotoxicity and impaired hemopoietic recovery following gamma irradiation. J. Immunol. 176, 6186–6193 (2006).

  72. 72.

    Cho, J. et al. IL-17 is essential for host defense against Staphylococcus aureus infection in mice. J. Clin. Invest. 120, 1762–1773 (2010).

  73. 73.

    Siegemund, S. et al. Production of IL-12, IL-23 and IL-27p28 by bone marrow-derived conventional dendritic cells rather than macrophages after LPS/TLR4-dependent induction by Salmonella Enteritidis. Immunobiology 212, 739–750 (2007).

  74. 74.

    Sellge, G. et al. Th17 cells are the dominant T cell subtype primed by Shigella flexneri mediating protective immunity. J. Immunol. 184, 2076–2085 (2010).

  75. 75.

    Griffiths, K. L. et al. Th1/Th17 cell induction and corresponding reduction in ATP consumption following vaccination with the novel Mycobacterium tuberculosis vaccine MVA85A. PLoS ONE 6, e23463 (2011).

  76. 76.

    Ma, C. S. et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J. Exp. Med. 205, 1551–1557 (2008).

  77. 77.

    Davis S., Schaller J. Job’s Syndrome: recurrent, “cold”, staphylococcal abcesses. Lancet. 1, 1013–1015 (1966).

  78. 78.

    Okada, S., Puel, A., Casanova, J. L. & Kobayashi, M. Chronic mucocutaneous candidiasis disease associated with inborn errors of IL-17 immunity. Clin. Transl. Immunol. 5, e114 (2016).

  79. 79.

    Gershon, R. & Kondo, K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 19, 723–737 (1970).

  80. 80.

    Green, D., Flood, P. & Gershon, R. Immunoregulatory T-cell pathways. Ann. Rev. Immunol. 1, 439–463 (1983).

  81. 81.

    Kronenberg, M. et al. RNA transcripts for I-J polypeptides are apparently not encoded between the I-A and I-E subregions of the murine major histocompatibility complex. Proc. Natl Acad. Sci. USA 80, 5704–5708 (1983).

  82. 82.

    Nishizuka, Y. & Sakakura, T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166, 753–755 (1969).

  83. 83.

    Penhale, W., Farmer, A., McKenna, R. & Irvine, W. Spontaneous thyroiditis in thymectomized and irradiated wistar rats. Clin. Exp. Immunol. 15, 225–236 (1973).

  84. 84.

    Takahashi, H. et al. Immunologic self-tolerance maintained by CD25+ CD4+ naturally anergic and suppressive T cells induction of autoimmune disease by breaking their anergic/suppressive state. Int. Immunol. 10, 1969–1980 (1998).

  85. 85.

    Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).

  86. 86.

    Asano, M., Toda, M., Sakaguchi, N. & Sakaguchi, S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 184, 387–396 (1996).

  87. 87.

    Malek, T. R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002).

  88. 88.

    Willerford, D. et al. Interleukin-2 receptor a chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521–530 (1995).

  89. 89.

    Setoguchi, R., Hori, S., Takahashi, T. & Sakaguchi, S. Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med. 201, 723–735 (2005).

  90. 90.

    Dwyer, C. et al. Altered homeostasis and development of regulatory T cell subsets represent an IL-2R-dependent risk for diabetes in NOD mice. Sci. Signal. 10, eeam9563 (2017).

  91. 91.

    Kurtulus, S. et al. TIGIT predominantly regulates the immune response via regulatory T cells. J. Clin. Invest. 125, 4053–4062 (2015).

  92. 92.

    Wang, R. et al. Expression of GARP selectively identifies activated human FOXP3+regulatory T cells. Proc. Natl Acad. Sci. USA 106, 13439–13444 (2009).

  93. 93.

    Rudensky, A. Y., Gavin, M. & Zheng, Y. FOXP3 and NFAT: partners in tolerance. Cell 126, 253–256 (2006).

  94. 94.

    Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142–1151 (2005).

  95. 95.

    Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

  96. 96.

    Feng, Y. et al. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158, 749–763 (2014).

  97. 97.

    Williams, L. M. & Rudensky, A. Y. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat. Immunol. 8, 277–284 (2007).

  98. 98.

    Getnet, D. et al. A role for the transcription factor helios in human CD4+CD25+regulatory cells. Mol. Immunol. 47, 1595–1600 (2010).

  99. 99.

    Elkord, E., Abd Al Samid, M. & Chaudhary, B. Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP. Oncotarget 6, 20026–20036 (2015).

  100. 100.

    Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppresive function of human CD4+T reg cells. J. Exp. Med. 203, 1701–1711 (2006).

  101. 101.

    Ono, M. & Tanaka, R. J. Controversies concerning thymus-derived regulatory T cells: fundamental issues and a new perspective. Immunol. Cell. Biol. 94, 3–10 (2016).

  102. 102.

    Zhou, L. et al. IL-6 programs Th1-7 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8, 967–974 (2007).

  103. 103.

    Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).

  104. 104.

    Ichiyama, K. et al. Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat. J. Biol. Chem. 283, 17003–17008 (2008).

  105. 105.

    Yang, X. P. et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat. Immunol. 12, 247–254 (2011).

  106. 106.

    Ding, Y., Xu, J. & Bromberg, J. S. Regulatory T cell migration during an immune response. Trends Immunol. 33, 174–180 (2012).

  107. 107.

    Kishore, M. et al. Regulatory T cell migration is dependent on glucokinase-mediated glycolysis. Immunity 47, 875–89 e10 (2017).

  108. 108.

    van der Vliet, H. J. & Nieuwenhuis, E. E. IPEX as a result of mutations in FOXP3. Clin. Dev. Immunol. 2007, 89017 (2007).

  109. 109.

    Lee, Y. K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009).

  110. 110.

    Maggi, L. et al. Distinctive features of classic and nonclassic (Th17 derived) human Th1 cells. Eur. J. Immunol. 42, 3180–3188 (2012).

  111. 111.

    Basdeo, S. A. et al. Ex-Th17 (Nonclassical Th1) cells are functionally distinct from classical Th1 and Th17 cells and are not constrained by regulatory T cells. J. Immunol. 198, 2249–2259 (2017).

  112. 112.

    Muranski, P. & Restifo, N. P. Essentials of Th17 cell commitment and plasticity. Blood 121, 2402–2414 (2013).

  113. 113.

    Yang, X. O. et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29, 44–56 (2008).

  114. 114.

    Komatsu, N. et al. Pathogenic conversion of Foxp3+T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62–68 (2014).

  115. 115.

    Downs-Canner, S. et al. Suppressive IL-17A(+)Foxp3(+) and ex-Th17 IL-17A(neg)Foxp3(+) Treg cells are a source of tumour-associated Treg cells. Nat. Commun. 8, 14649 (2017).

  116. 116.

    Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500–508 (2002).

  117. 117.

    Viglietta, V., Baecher-Allan, C., Weiner, H. L. & Hafler, D. A. Loss of functional suppression by CD4+CD25+regulatory T cells in patients with multiple sclerosis. J. Exp. Med. 199, 971–979 (2004).

  118. 118.

    Martin, D. A. et al. The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings. J. Invest. Dermatol. 133, 17–26 (2013).

  119. 119.

    Kaneko S. et al. The RORgammat-CCR6-CCL20 axis augments Th17 cells invasion into the synovia of rheumatoid arthritis patients. Mod. Rheumatol. 2017:1–26.

  120. 120.

    Skroza, N. et al. Correlations between psoriasis and inflammatory bowel diseases. Biomed. Res. Int. 2013, 983902 (2013).

  121. 121.

    Martin, J. C., Baeten, D. L. & Josien, R. Emerging role of IL-17 and Th17 cells in systemic lupus erythematosus. Clin. Immunol. 154, 1–12 (2014).

  122. 122.

    Cao, Y. et al. Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Sci. Transl. Med. 7, 287ra74 (2015).

  123. 123.

    Matusevicius, D. et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult. Scler. 5, 101–104 (1999).

  124. 124.

    Hu, D. et al. Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis. Nat. Commun. 8, 1600 (2017).

  125. 125.

    Putheti, P., Pettersson, A., Soderstrom, M., Link, H. & Huang, Y. Circulating CD4+CD25+T regulatory cells are not altered in multiple sclerosis and unaffected by disease-modulating drugs. J. Clin. Immunol. 24, 155–161 (2004).

  126. 126.

    Segal, B. M. et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 7, 796–804 (2008).

  127. 127.

    Havrdova, E. et al. Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: results from a randomized, proof-of-concept study. J. Neurol. 263, 1287–1295 (2016).

  128. 128.

    Jewell C., Tostanoski L., Royal W. Self-assembly of immune signals to induce and control tolerance. J Immunol. 2017;198 (1 Supplement) 81.3.

  129. 129.

    Fitch, E., Harper, E., Skorcheva, I., Kurtz, S. & Blauvelt, A. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr. Rheumatol. Rep. 9, 461–467 (2007).

  130. 130.

    Kagami, S., Rizzo, H. L., Lee, J. J., Koguchi, Y. & Blauvelt, A. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J. Invest. Dermatol. 130, 1373–1383 (2010).

  131. 131.

    Wilke, C. M., Bishop, K., Fox, D. & Zou, W. Deciphering the role of Th17 cells in human disease. Trends Immunol. 32, 603–611 (2011).

  132. 132.

    Harper, E. G. et al. Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis. J. Invest. Dermatol. 129, 2175–2183 (2009).

  133. 133.

    Johansen, C. et al. Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br. J. Dermatol. 160, 319–324 (2009).

  134. 134.

    Kryczek, I. et al. et al. Induction of IL-17+T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis. J. Immunol. 181, 4733–4741 (2008).

  135. 135.

    Ramirez-Carrozzi, V. et al. IL-17C regulates the innate immune function of epithelial cells in an autocrine manner. Nat. Immunol. 12, 1159–1166 (2011).

  136. 136.

    Ciric, B., El-behi, M., Cabrera, R., Zhang, G. X. & Rostami, A. IL-23 drives pathogenic IL-17-producing CD8+T cells. J. Immunol. 182, 5296–5305 (2009).

  137. 137.

    Nograles, K. E. et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br. J. Dermatol. 159, 1092–1102 (2008).

  138. 138.

    Sugiyama, H. et al. Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J. Immunol. 174, 164–173 (2004).

  139. 139.

    Bovenschen, H. et al. Foxp3+regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J. Inv Derm. 131, 1853–1860 (2011).

  140. 140.

    Langley R. G. et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial. Br. J. Dermatol. 2017.

  141. 141.

    Blanco, F. J. et al. Secukinumab in active rheumatoid arthritis: a phase III randomized, double-blind, active comparator- and placebo-controlled study. Arthritis Rheumatol. 69, 1144–1153 (2017).

  142. 142.

    Sarkar, S. & Fox, D. A. Targeting IL-17 and Th17 cells in rheumatoid arthritis. Rheum. Dis. Clin. North. Am. 36, 345–366 (2010).

  143. 143.

    Haque, M., Fino, K., Lei, F., Xiong, X. & Song, J. Utilizing regulatory T cells against rheumatoid arthritis. Front Oncol. 4, 209 (2014).

  144. 144.

    Samson, M. et al. Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum. 64, 2499–2503 (2012).

  145. 145.

    Boden, E. K. & Snapper, S. B. Regulatory T cells in inflammatory bowel disease. Curr. Opin. Gastroenterol. 24, 733–741 (2008).

  146. 146.

    Sandborn, W. et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s Disease. Gastroenterology 135, 1130–1141 (2008).

  147. 147.

    Plevy, S. et al. A phase I study of visilizumab, a humanized anti-CD3 monoclonal antibody, in severe steroid-refractory ulcerative colitis. Gastroenterology 133, 1414–1422 (2007).

  148. 148.

    Fujino, S. et al. Increased expression of interleukin 17 i inflammatory bowel disease. Gut 52, 65–70 (2003).

  149. 149.

    Kyttaris, V. C., Zhang, Z., Kuchroo, V. K., Oukka, M. & Tsokos, G. C. Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice. J. Immunol. 184, 4605–4609 (2010).

  150. 150.

    Lee, H. Y. et al. Altered frequency and migration capacity of CD4+CD25+regulatory T cells in systemic lupus erythematosus. Rheumatology 47, 789–794 (2008).

  151. 151.

    Wang, D. et al. Allogenic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience. Cell Transp. 22, 2267–2277 (2013).

  152. 152.

    Kleinewietfeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518–522 (2013).

  153. 153.

    Wilck, N. et al. Salt-responsive gut commensal modulates Th17 axis and disease. Nature 551, 585–589 (2017).

  154. 154.

    Wenzel, U. et al. Immune mechanisms in arterial hypertension. J. Am. Soc. Nephrol. 27, 677–686 (2016).

  155. 155.

    Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).

  156. 156.

    Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

  157. 157.

    Parsonnet, J. et al. Helicobacter Pylori infection and the risk of gastric carcinoma. N. Engl. J. Med. 325, 1127–1131 (1991).

  158. 158.

    Munoz, N., Bosch, F., De Sanjose, S. & Shah, K. The role of HPV in the etiology of cervical cancer. Mutat. Res. 305, 293–301 (1994).

  159. 159.

    Sfanos, K. S. et al. Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin. Cancer Res. 14, 3254–3261 (2008).

  160. 160.

    Kryczek, I. et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114, 1141–1149 (2009).

  161. 161.

    Murugaiyan, G. & Saha, B. Protumor vs antitumor functions of IL-17. J. Immunol. 183, 4169–4175 (2009).

  162. 162.

    Takahashi, H., Numasaki, M., Lotze, M. T. & Sasaki, H. Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells. Immunol. Lett. 98, 189–193 (2005).

  163. 163.

    Benevides, L. et al. IL17 promotes mammary tumor progression by changing the behavior of tumor cells and eliciting tumorigenic neutrophils recruitment. Cancer Res. 75, 3788–3799 (2015).

  164. 164.

    Tosolini, M. et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 71, 1263–1271 (2011).

  165. 165.

    Martin-Orozco, N., Chung, Y., Chang, S. H., Wang, Y. H. & Dong, C. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur. J. Immunol. 39, 216–224 (2009).

  166. 166.

    Duan, M. et al. Disturbed Th17/Treg balance in patients with non-small cell lung cancer. Inflammation 38, 2156–2165 (2015).

  167. 167.

    Horlock, C. et al. The effects of trastuzumab on the CD4+CD25+FoxP3+ and CD4+IL17A+ T-cell axis in patients with breast cancer. Br. J. Cancer. 100, 1061–1067 (2009).

  168. 168.

    Tang, Y. et al. An increased abundance of tumor-infiltrating regulatory T cells is correlated with the progression and prognosis of pancreatic ductal adenocarcinoma. PLoS ONE 9, e91551 (2014).

  169. 169.

    Shou, J., Zhang, Z., Lai, Y., Chen, Z. & Huang, J. Worse outcome in breast cancer with higher tumor-infiltrating FOXP3+Tregs: a systematic review and meta-analysis. BMC Cancer 16, 687 (2016).

  170. 170.

    Alessandra Metelli et al. Surface Expression of TGFÎ2 Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer. Cancer Research. 76, 7106–7117 (2016).

  171. 171.

    Budhu B. et al. Blockade of surace-bound TGF-B on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment. Sci Signal. 10, eaak9702 (2017).

  172. 172.

    Maj, T. et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat. Immunol. 18, 1332–1341 (2017).

  173. 173.

    Leone, R. D., Lo, Y. C. & Powell, J. D. A2aR antagonists: next generation checkpoint blockade for cancer immunotherapy. Comput. Struct. Biotechnol. J. 13, 265–272 (2015).

  174. 174.

    Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281 (2012).

  175. 175.

    Gattinoni, L. et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+T cells. J. Clin. Invest. 115, 1616–1626 (2005).

  176. 176.

    Tran, E. H. et al. Cancer immunotherapy based on mutation-specific CD4+T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).

  177. 177.

    Bailey, S. R. et al. Human CD26 high T cells elicit tumor immunity against multiple malignancies via enhanced migration and persistance. Nat. Commun. 8, 1961 (2017).

  178. 178.

    Muranski, P. et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 112, 362–372 (2008).

  179. 179.

    Muranski, P. et al. Th17 cells are long lived and retain a stem cell-like molecular signature. Immunity 35, 972–985 (2011).

  180. 180.

    Martin-Orozco, N. et al. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31, 787–798 (2009).

  181. 181.

    Xie, Y. et al. Naive tumor-specific CD4(+) T cells differentiated in vivo eradicate established melanoma. J. Exp. Med. 207, 651–667 (2010).

  182. 182.

    Paulos C. M. et al. The inducible costimulator (ICOS) is critical for the development of human Th17 cells. Sci. Transl. Med. 2, 55ra78 (2018).

  183. 183.

    Kryczek, I. et al. Human TH17 cells are long-lived effector memory cells. Sci. Transl. Med. 3, 104ra0 (2011).

  184. 184.

    Yu, Y. et al. Abundant c-Fas-associated death domain-like interleukin-1-converting enzyme inhibitory protein expression determines resistance of T helper 17 cells to activation-induced cell death. Blood 114, 1026–1028 (2009).

  185. 185.

    Bowers, J. S. et al. Th17 cells are refractory to senescence and retain robust antitumor activity after long-term ex vivo expansion. JCI Insight 2, e90772 (2017).

  186. 186.

    Bailey, S. R. et al. Th17 cells in cancer: the ultimate identity crisis. Front. Immunol. 5, 276 (2014).

  187. 187.

    Webb E. S. et al. Immune checkpoint inhibitors in cancer therapy. J. Biomed. Res. 0, 1–10 2017.

  188. 188.

    June, C. H., Warshauer, J. T. & Bluestone, J. A. Corrigendum: Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat. Med. 23, 1004 (2017).

  189. 189.

    Vanderlugt, C. L. & Miller, S. D. Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat. Rev. Immunol. 2, 85–95 (2002).

  190. 190.

    Linardou, H. & Gogas, H. Toxicity management of immunotherapy for patients with metastatic melanoma. Ann. Transl. Med. 4, 272 (2016).

  191. 191.

    Muro, K. et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 17, 717–726 (2016).

  192. 192.

    Shi, V. J. et al. Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell death 1 and anti-programmed cell death ligand 1 immunotherapy. JAMA Dermatol. 152, 1128–1136 (2016).

  193. 193.

    Hwang, S. J. et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort. J. Am. Acad. Dermatol. 74, 455–61 e1 (2016).

  194. 194.

    Sibaud, V. et al. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr. Opin. Oncol. 28, 254–263 (2016).

  195. 195.

    Hua, C. et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 152, 45–51 (2016).

  196. 196.

    Jour, G. et al. Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions. J. Cutan. Pathol. 43, 688–696 (2016).

  197. 197.

    Parakh, S., Nguyen, R., Opie, J. & Andrews, M. Late presentation of generalised bullous pemphigoid-like reaction in a patient treated with pembrolizumab for metastatic melanoma. Australas. J. Dermatol. 58, 109–112 (2017).

  198. 198.

    Bonigen, J. et al. Anti-PD1-induced psoriasis: a study of 21 patients. J. Eur. Acad. Dermatol. Venereol. 31, e254–e257 (2017).

  199. 199.

    Maker, A. et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann. Surg. Oncol. 12, 1005–1016 (2005).

  200. 200.

    Yang, J. et al. Ipilumumab (Anti-CTLA4 Antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J. Immunother. 30, 825–830 (2007).

  201. 201.

    Di Giacomo, A. M., Biagioli, M. & Maio, M. The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications. Semin. Oncol. 37, 499–507 (2010).

  202. 202.

    Sznol, M. et al. Pooled analysis safety profile of nivolumab and ipilumumab combination therapy in patients with advanced melanoma. J. Clin. Oncol. 35, 3815–3822 (2017).

  203. 203.

    Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

  204. 204.

    Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).

  205. 205.

    Hassel, J. C. et al. Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): evaluation and management of adverse drug reactions. Cancer Treat. Rev. 57, 36–49 (2017).

  206. 206.

    Weber, J. S. et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J. Clin. Oncol. 26, 5950–5956 (2008).

  207. 207.

    Attia, P. et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J. Clin. Oncol. 23, 6043–6053 (2005).

  208. 208.

    Phan, G. Q. et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl Acad. Sci. USA 100, 8372–8377 (2003).

  209. 209.

    Beck, K. E. et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J. Clin. Oncol. 24, 2283–2289 (2006).

  210. 210.

    Downey, S. G. et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin. Cancer Res. 13, 6681–6688 (2007).

  211. 211.

    Tarhini, A. A. et al. Baseline circulating IL-17 predicts toxicity while TGF-beta1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma. J. Immunother. Cancer 3, 39 (2015).

  212. 212.

    Yurkovetsky, Z. R. et al. Multiplex analysis of serum cytokines in melanoma patients treated with interferon-alpha2b. Clin. Cancer Res. 13, 2422–2428 (2007).

  213. 213.

    Esfahani, K. & Miller, W. Reversal of autoimmune toxicity and loss of tumor response by interleukin-17 blockade. N. Engl. J. Med. 376, 1989–1991 (2017).

  214. 214.

    Krieg C. et al. High dimensional analysis of the immune landscape during anti-PD-1 immunotherapy of melanoma predicts responsiveness. Nat. Med. 24, 144–153 (2018).

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This work was supported in part by NIH Training grant T32 GM08716 to H.M.K., NIH Fellowship grant F31 CA192787 to S.R.B., NIH Training grant T32 AI132164-01 to C.J.D., NCI Grants R01 CA175061 and R01 CA208514, KL2 South Carolina Clinical & Translational Research grant UL1 TR000062, ACS-IRG grant 016623-004 and MUSC Start-up funds to C.M.P.

Author information


  1. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA

    • Hannah M. Knochelmann
    • , Connor J. Dwyer
    • , Stefanie R. Bailey
    • , Sierra M. Amaya
    •  & Chrystal M. Paulos
  2. Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, USA

    • Hannah M. Knochelmann
    • , Connor J. Dwyer
    • , Stefanie R. Bailey
    • , Sierra M. Amaya
    • , Dirk M. Elston
    • , Joni M. Mazza-McCrann
    •  & Chrystal M. Paulos


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The authors declare that they have no competing interest.

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Correspondence to Hannah M. Knochelmann or Chrystal M. Paulos.

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