The current review reveals the seven subclasses of CD4+ T helper cells, i.e. Th1, Th2, Th9, Th17, Th22, regulatory T cells and Tfh, the cytokines produced by them and their role in tumor microenvironment. Main attention was paid to IL-17 and Th17 cells. IL-17-producing cells were described, among which were Treg17 cells and Tc17 cells. The transcription factors, engaged in the activation of Th17 cell differentiation were reviewed. It was shown that Th17 cells might possess regulatory functions in tumor microenvironments that directs toward immunosuppression. The reciprocity between Treg and Th17 cells is realized when the production of a large amount of TGF-β in tumors causes Treg cell differentiation, and the addition of IL-6 shifts the differentiation of naïve T cells to Th17 cells. The main pro-tumor role of IL-17 is the promotion of tumor angiogenesis through stimulation of fibroblasts and endothelial cells. The antitumor functions of IL-17 are associated with enhancement of cytotoxic activity of tumor specific CTL cells and with angiogenesis that provide channels through which immune cells might invade tumor and promote antitumor immunity.
1. Romagnani S. Human Th17 cells. Arthritis Research and Therapy 2008;10:206-2013.
2. Romagnani S, Maggi E, Liotta F, Cosmi L, Annunziato F. Properties and origin of human Th17 cells. Molecular Immunology 2009;47:3-7.
3. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol 2010;28:445-489.
4. Cosmi L, Maggi L, Santarlasci V, Liotta F, Annunziato F. T helper cells plasticity in inflammation. Cytometry Part A 2014;85A;36-42.
5. Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, Parente E, Fili L, Ferri S, Frosali F, Giudici F, Romagnani P, Parronchi P, Tonelli F, Maggi E, Romagnani S. Phenotypic and functional features of human Th17 cells. J Exp Med 2007;204:1849-1861.
6. Hammerich L, Heymann F, Tacke F. Role of IL-17 and Th17 cells in liver diseases. Clinical and Developmental Immunology 2011; 2011:345803.
7. Ivanova EA, Orekhov AN. T helper lymphocyte subsets and plasticity in autoimmunity and cancer: an overview. BioMed Research International 2015, article ID 327470, 9 pages http://dx.doi.org/10.1155/2015/327470
8. Golubovskaya V, Wu L. Different subsets of T cells memory, effector functions, and CAR-T immunotherapy. Cancers 2016;8(36), doi:
9. Mosmann TR, Cherwinski H, Bond MW. Two types of murine helper T cell clone. I. Defi nition according to profi les of lymphokine activities and secreted proteins. Journal of Immunology 1986;136(7):2348-2357.
10. Cohen PA, Peng L, Plautz GE, Kim JA,Weng DE, Shu S. CD4+ T cells in adoptive immunotherapy and the indirect mechanism of tumor rejection. Crit Rev Immunol 2000;20:17-56.
11. Kalams SA, Walker BD. The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses. J Exp Med 1998;188:2199-2204.
12. Ossendorp F, Toes RE, Offringa R, van der Burg SH, Melief CJ. Importance of CD(4+) T helper cell responses in tumor immunity. Immunol Lett 2000;74:75-79.
13. Murphy KM, Reiner SL. The lineage decisions of helper T cells. Nature Reviews Immunology 2002;2(12):933-944.
14. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996;383:787-793.
15. O’Garra A, Arai N. The molecular basis of T helper 1 and T helper 2 cell differentiation. Trends in Cell Biology 2000;10(12):542-550.
16. Amsen D, Spilianakis CG, Flavell RA. How are Th1 and Th2 effector cells made. Curr Opin Immunol 2009;21:153-160.
17. Kaplan MH, Hufford MM, Olson MR. The development and in vivo function of T helper 9 cells. Nature Reviews Immunology 2015;15(5):295-307.
18. Neil DR, McKenzie ANJ. TH9: the latest addition to the expanding repertoire of IL-25 targets. Immunology and Cell Biology 2010;88:502-504.
20. Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H. Identifi cation of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH17, TH1 and TH2 cells. Nature Immunology 2009;10(8):864-871.
21. Zhuang Y, Peng L-S, Zhao Y-L, Shi Y, Mao XH, Guo G, Chen W, Liu XF, Zhang JY, Liu T, Luo P, Yu PW, Zou QM. Increased intratumoral IL-22-producing CD4+ T cells and Th-22 correlate with gastric cancer progression and predict poor patient survival. Cancer Immunology, Immunotherapy 2012;61(11):1965-1975.
22. Kobold S, Volk S, Clauditz T, Kupper NJ, Minner S, Tufman A, Duwell P, Lindner P, Koch I, Heidegger S, Rothenfuβer S, Schnurr M. Interleukin-22 is frequently expressed in small- and large- cell lung cancer and promotes growth in chemotherapy-resistant cancer cells. Journal of Thoracic Oncology 2013;8(8):1032-1042.
23. Jia L, Wu C. The biology and functions of Th22 cells. In: T Helper Cell Differentiation and Their Function, 2014, vol. 841 of Advances in Experimental Medicine and Biology pp. 209-230.
24. Ma CS, Deenick EK, Batten M, Tangye SG. The origins, function, and regulation of T follicular helper cells. The Journal of Experimental Medicine 2012;209(7):1241-1253.
25. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008;133:775 - 787.
26. Numasaki M, Fukushi J-I, Ono M, Narula SK, Zavodny PJ, Kudo T, Robbins PD, Tahara H, Lotze PJ. Interleukin-17 promotes angiogenesis and tumor growth. Blood 2003;101:2620-2627.
27. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer 2010;127:759-767.
28. Li MO, Sanjabi S, Flavell R. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 2006;25(3):455-471.
29. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature immunology 2003;4(4):330-336.
30. Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Review 2003;14:155-174.
31. Takahashi N, Vanlaere I, de Rycke R, et al. IL-17 produced by Paneth cells drives TNF-induced shock. J Exp Med 2008;205 (8):1755-1761.
32. Murugaiyan G, Saha B. Protumor vs Antitumor functions of IL-17. J Immunol 2009;183:4169- 4175.
33. Wu D, Wu P, Huang Q, Liu Y, Ye J, Huang J. Interleukin-17: a promoter in colorectal cancer progression. Clinical and Developmental Immunology 2013; article ID 436307: 7.
34. Li L, Boussiotis V. The role of IL-17-producing Foxp3+ CD4+ T cells in infl ammatory bowel disease and colon cancer. Clin Immunol 2013;148(2): doi:
35. Huber M, Heink S, Pagenstecher A, et al. IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis. J Clin Invest 2013;123(1):247-260.
36. Segura E, Touzot M, Bohineust A, Cappuccio A, Chiocchia G, Hosmalin A, Dalod M, Soumelis V, Amigorena S. Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity. 2013 Feb 21;38(2):336-48.
37. Jovanovich DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, Mineau F, Pelletier JP. IL-17 stimulates the production and expression of proinfl ammatory cytokines, IL-beta and TNFalpha, by human macrophages. J Immunol. 1998 Apr 1;160(7):3513-21.
38. Chen Z, O‘Shea JJ. Th17 cells: a new fate for differentiating helper T cells. Immunol Res. 2008;41(2):87-102.
39. Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupé P, Barillot E, Soumelis V. A critical function for transforming growth factor-beta, interleukin 23 and proinfl ammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol. 2008 Jun;9(6):650-7.
40. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of proinfl ammatory IL-17+ T helper cells. Cell. 2006 Sep 22;126(6):1121-33.
41. Acosta-Rodriguez L, Rivino J, Geginat D, Jarrossay M, Gattorno A, Lanzavecchia M, Sallusto F, Napolitani F. Surface phenotype and antigenic specifi city of human interleukin 17-producing T helper memory cells. Nat Immunol 2007; 8:639-646.
42. Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 2008;9:641-649.
43. Mangan PR, Harrington LE, O‘Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006 May 11;441(7090):231-4.
44. Torchinsky M, Blander J. T helper cells: discovery, function, and physiological trigger. Cell Mol Life Sci 2010;67:1407-1421.
45. Quyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in infl ammation. Immunity 2008;28(4):454-467.
46. Su X, Ye J, Hsueh EC, Zhang , Hoft DF, Peng G. Tumor microenvironments direct the recruitment and expansion of human Th17 cells. The Journal of Immunology 2010;184:1630-1641.
47. Laurence A, O’Shea JJ. T(H)-17 differentiation: of mice and men. Nat Immunol 2007;8:903-905.
48. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron JC, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal Malefyt R. Development, cytokine profi le and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007 Sep;8(9):950-7.
49. Van Beelen AJ, Zelinkova Z, Taanman-Kueter EW, Muller FJ, Hommes DW, Zaat SA, Kapsenberg ML, de Jong EC. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity 2007;27:660-669.
50. Miyahara Y, Odunsi K, Chen G, Peng J, Matsuzaki J, Wang RF. Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer. Proc Natl Acad Sci USA 2008;105:15505-15510.
51. Steiner GE, Newman ME, Paikl D, Stix U, Memaran-Dagla N, Lee C, Marberger MJ. Expression and function of pro-infl ammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate. Prostate 2003;56:171-182.
52. Zhang B, Rong G, Wei H, Zhang M, Bi J, Ma L, Xue X, Wei G, Liu X, Fang G. The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun 2008;374:533-537.
53. McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ. TGF-β 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 2007;8:1390-1397.
54. Ishida T, Ishii T, Inagaki A, Yano H, Komatsu H, Iida S, Inagaki H, Ueda R. Specifi c recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilige. Cancer Res 2006;66:5716-5722.
55. Liu SJ, Tsai JP, Shen CR, Sher YP, Hsieh CL, Yeh YC, Chou AH, Chang SR, Hsiao KN, Yu FW, Chen HW. Induction of a distinct CD8 Tnc17 subset by transforming growth factor-β and interleukin-6. J Leukocyte Biol 2007;82:354-360.
56. Wang J, Xu K, Wu J, Luo C, Li Y, Wu X, Gao H, Feng G, Yuan B-Z. The changes of Th17 cells and the related cytokines in the progression of human colorectal cancers. BMC Cancer 2012;12:418-428.
57. Liao R, Sun J, Wu H, Yi Y, Wang J-X, He H-W, Cai X-Y, Zhou J, Cheng Y-F, Fan J, Qiu S-J. High expression of IL-17 and IL17RE associate with poor prognosis of hepatocellular carcinoma. Journal of Experimental and Clinical Cancer Research 2013;32:3-14.
58. Lim HW, Lee J, Hillsamer P, Kim CH. Human Th17 cells share major traffi cing receptors with both polarized effector T cells and FOXP3+ regulatory T cells. J Immunol 2008;180:122-129.
59. McGeachy MJ, Cua DJ. Th17 cell differentiation: the long and winding road. Immunity 2008;28:445-453.
60. Kryczek I, Wei S, Zou L, Altuwaijri S, Szeliga W, Kolls J, Chang A, Zou W. Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol 2007;178:6730-6733.
61. Koenen HJ, Smeets RL, Vink PM, van Rijssen E, Boots AM, Joosten I. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 2008;112:2340-2352.
62. Kryczek I, Wu K, Zhao E, Wei S, Vatan L, Szeliga W, Huang E, Greenson J, Chang A, Rolinski J, Radwan P, Fang J, Wang G, Zou W. IL-17+ regulatory T cells in the microenvironments of chronic infl ammation and cancer. J Immunol 2011;186:4388-4395.
63. Ma C, Dong X. Colorectal cancer-derived Foxp3+IL-17+ T cells suppress tumor specific CD8+ T cells. Scandinavian Journal of Immunology 2011:47-51.
64. Yang S, Wang B, Guan C, Wu B, Cai C, Wang M, Zhang B, Liu T, Yang P. Foxp3+IL-17+ T cells promote development of cancer-initiating cells in colorectal cancer. Journal of Leukocyte Biology 2011;89:85-91.
65. Massague J. TGF-β in cancer. Cell 2008;134:215-230.
66. Liu J, Duan Y, Cheng X, Chen X, Xie W, Long H, Lin Z, Zhu B. IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma. Biochem Biophys Res Commun 2011;407:348-354.
67. Blankenstein T, Qin Z. The role of IFN-γ in tumor transplantation immunity and inhibition of chemical carcinogenesis. Curr Opin Immunol 2003;15:148-154.
68. Nam JS, Terabe M, Kang MJ, Chae H, Voong N, Yang YA, Laurence A, Michalowska A, Mamura M, Lonning S, Berzofsky JA, Wakefi eld LM. Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17. Cancer Res. 2008 May 15;68(10):3915-23.
69. Kortylewski M, Xin H, Kujawski M, Lee H, Liu Y, Harris T, Drake C, Pardoll D, Yu H. Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell 2009;15:114-123.
70. Lo CH, Lee SC, Wu PY, Pan WY, Su J, Cheng CW, Roffl er SR, Chiang BL, Lee CN, Wu CW, Tao MH. Antitumor and antimetastatic activity of IL-23. J Immunol 2003;171:600-607.
71. Shan BE, Hao JS, Li QX, Tagawa M. Antitumor activity and immune enhancement of murine interleukin-23 expressed in murine colon carcinoma cells. Cell Mol Immunol 2006;3:47-52.
72. Chizzolini C, Chicheportiche R, Alvarez M, de Rham C, Roux-Lombard P, Ferrari-Lacraz S, Dayer JM. Prostaglandin E2 synergistically with interleukin-23 favors human Th17 expansion. Blood 2008;112:3696-3703.
73. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007;317:256-260.
74. Zhou X, Bailey-Bucktrout S, Jeker LT, Bluestone JA-b. Plasticity of CD4+FoxP3+ T cells. Curr Opin Immunol 2009;21:281-285.
75. Zhou L, Chong MM, Littman DR-a. Plasticity of CD4+ T cell lineage differentiation. Immunity 2009;30:646-655.
76. Beriou G, Costantino CM, Ashley CW, Yang L, Kuchroo VK, Baecher-Allan C, Hafl er DA. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 2009;113:4240-4249.
77. Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, Shah B, Chang SH, Schluns KS, Watowich SS, et al. Molecular antagonism and plasticity of regulatory and infl ammatory T cell programs. Immunity 2008;29:44-56.
78. Zou W. Regulatory T cells, tumor immunity and immunotherapy. Nat Rev Immunol 2006;6:295-307.
79. Takahashi H, Numasaki M, Lotze T, Sasaki H. Interleukin-17 enhances bFGF-, HGF- and VEGFinduced growth of vascular endothelial cells. Immunol Lett 2005;98:189-193.
80. Jeon SH, Chae BC, Kim HA, Seo GY, Seo DW, Chun GT, Kim NS, Yie SW, Byeon WH, Eom SH, Ha KS, Kim YM, Kim PH. Mechanisms underlying TGF-beta1-induced expression of VEGF and Flk-1 in mouse macrophages and their implications for angiogenesis. J Leukoc Biol. 2007 Feb;81(2):557-66.
81. Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res 2008;14:6735-6741.
82. Lee JW, Wang P, Kattah MG, Youssef S, Steinman L, DeFea K, Straus DS. Differential regulation of chemokines by IL-17 in colonic epithelial cells. J Immunol. 2008 Nov 1;181(9):6536-45.
83. Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A, Paulos CM, Palmer DC, Touloukian CE, Ptak K, Gattinoni L, Wrzesinski C, Hinrichs CS, Kerstann KW, Feigenbaum L, Chan CC, Restifo NP. Tumor-specifi c Th17-polarized cells eradicate large established melanoma. Blood. 2008 Jul 15;112(2):362-73.
84. Benchetrit F, Ciree A, Vives V, Warnier G, Gey A, Sautes-Fridman C, Fossiez F, Haicheur N, Fridman WH, Tartour E. Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood 2002;99:2114-2121.
85. De Simone V, Franze E, Ronchetti G, Colantoni A, Fantini MC, Di Fusco D, Sica GS, Sileri P, Mac- Donald TT, Pallone F, Monteleone G, Stolfi C. Oncogene 2014;1-11.
86. Zamarron BF, Chen WJ. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci 2011;7(5):651-658.