Th9 Cells As a New Player in Inflammatory Skin Disorders
CD4+T cells are composed of different subpopulations that differ in developmental pathways, surface markers, and their products. Among the catalog of these cells is Th9 cell subset that has a great capacity of Interleukin (IL)-9 production. They could be involved in the pathogenic or protective immune responses. Therefore, it is important to know how Th9 cells and cytokines influence the function of the human immune system as multitasking machinery, both in isolation or after the interaction with other surrounding cells. Since an important characteristic of Th9 cells is their tropism for skin, this article reviews the physiological and pathophysiological functions of Th9 and its cytokines under normal conditions and inflammatory skin disorders.
2. Xiao X, Balasubramanian S, Liu W, Chu X, Wang H, Taparowsky EJ, et al. OX40 signaling favors the induction of TH9 cells and airway inflammation. Nat Immunol 2012; 13(10):981–90.
3. Li H, Edin ML, Bradbury JA, Graves JP, DeGraff LM, Gruzdev A et al. Cyclooxygenase-2 Inhibits T Helper Cell Type 9 Differentiation during Allergic Lung Inflammation via Down-regulation of IL-17RB. Am J Respir Crit Care Med 2013; 187(8):812–22.
4. Kerzerho J, Maazi H, Speak AO, et al. Programmed cell death ligand 2 regulates TH9 differentiation and induction of chronic airway hyperreactivity. J Allergy Clin Immunol 2013; 131(4): 1048–57.
5. Pasparakis M, Haase I, Nestle FO. Mechanisms regulating skin immunity and inflammation. Nat Rev Immunol 2014; 14(5):289-301.
6. Heath WR, Carbone FR. The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells. Nat Immunol 2013; 14(10):978-85.
7. Yazdi AS, Röcken M, Ghoreschi K. Cutaneous immunology: basics and new concepts. Semin Immunopathol 2016; 38(1):3-10.
8. Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D et al. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nat Immunol 2007; 8(3):285-93.
9. Takeda A, Sasaki N, Miyasaka M. The molecular cues regulating immune cell trafficking. Proc Jpn Acad Ser B Phys Biol Sci 2017; 93(4):183-95.
10. Mueller SN, Zaid A, Carbone FR. Tissue-resident T cells: dynamic players in skin immunity. Front Immunol 2014; 5:332.
11. Hochheiser K, Bedoui S, Gebhardt T. Multilayered T-cell memory in human skin. Ann Transl Med 2015; 3(20):311.
12. Ivanova EA, Orekhov AN. T Helper Lymphocyte Subsets and Plasticity in Autoimmunity and Cancer: An Overview. Biomed Res Int 2015; 2015:327470.
13. Yao C, Zurawski SM, Jarrett ES, Chicoine B, Crabtree J, Peterson EJ et al. Skin dendritic cells induce follicular helper T cells and protective humoral immune responses. J Allergy Clin Immunol 2015; 136(5):1387-97.e1-7
14. Wang JY, Nguyen GH, Ruan J, Magro CM. Primary cutaneous follicular helper T-Cell lymphoma: A case series and review of the literature. Am J Dermatopathol 2017; 39(5):374-83.
15. Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 2015; 74(1):5-17.
16. Eyerich S, Zielinski CE. Defining Th-cell subsets in a classical and tissue-specific manner: Examples from the skin. Eur J Immunol 2014; 44(12):3475-83.
17. Nomura T, Kabashima K, Miyachi Y. The panoply of αβT cells in the skin. J Dermatol Sci 2014; 76(1):3-9.
18. Hültner L, Druez C, Moeller J, Uyttenhove C, Schmitt E, Rüde E et al. Mast cell growth-enhancing activity (MEA) is structurally related and functionally identical to the novel mouse T cell growth factor P40/TCGFIII (interleukin 9). Eur J Immunol 1990; 20(6):1413-6.
19. Uyttenhove C, Simpson RJ, Van Snick J. Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity. Proc Natl Acad Sci U S A 1988; 85(18): 6934-8.
20. Van Snick J, Goethals A, Renauld JC, Van Roost E, Uyttenhove C, Rubira MR et al. Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40). J Exp Med 1989; 169(1):363-8.
21. Kaplan MH. The transcription factor network in Th9 cells. Semin Immunopathol 2017; 39(1):11-20.
22. O'Shea JJ, Lahesmaa R, Vahedi G, Laurence A, Kanno Y. Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol 2011; 11(4):239-50.
23. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol 2010; 28:445-89.
24. Goswami R, Kaplan MH. Gcn5 is required for PU.1-dependent IL-9 induction in Th9 cells. J Immunol 2012; 189(6):3026-33.
25. Zhang Y, Zhang Y, Gu W, Sun B. TH1/TH2 cell differentiation and molecular signals. Adv Exp Med Biol 2014; 841:15-44.
26. Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 2010; 33(2):192-202.
27. Goswami R, Jabeen R, Yagi R, Lingnau K, Reuter S, Grebe N et al. STAT6-dependent regulation of Th9 development. J Immunol 2012; 188(3):968-75.
28. Schmitt E, Germann T, Goedert S, Hoehn P, Huels C, Koelsch S et al. IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma. J Immunol 1994; 153(9):3989-96.
29. Angkasekwinai P, Chang SH, Thapa M, Watarai H, Dong C. Regulation of IL-9 expression by IL-25 signaling. Nat Immunol 2010; 11(3):250-6.
30. Wong MT, Ye JJ, Alonso MN, Landrigan A, Cheung RK, Engleman E et al. Regulation of human Th9 differentiation by type I interferons and IL-21. Immunol Cell Biol 2010; 88(6):624-31.
31. Garo LP, Beynon V, Murugaiyan G. Flow Cytometric Assessment of STAT Molecules in Th9 Cells. Methods Mol Biol 2017; 1585:127-140.
32. Clark RA. Skin-resident T cells: the ups and downs
of on site immunity. J Invest Dermatol 2010; 130(2):362-70.
33. Schlapbach C, Gehad A, Yang C, Watanabe R, Guenova E, Teague JE et al. Human TH9 cells are skin-tropic and have autocrine and paracrine proinflammatory capacity. Sci Transl Med 2014; 6(219):219ra8.
34. Yang XR, Pfeiffer RM, Wheeler W, Yeager M, Chanock S, Tucker MA et al. Identification of modifier genes for cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations. Int J Cancer 2009; 125(12):2912-7.
35. Purwar R, Schlapbach C, Xiao S, Kang HS, Elyaman W, Jiang X et al. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 2012; 18(8):1248-53.
36. Nonomura Y, Otsuka A, Nakashima C, Seidel JA, Kitoh A, Dainichi T et al. Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients. Oncoimmunology 2016; 5(12):e1248327.
37. Végran F, Apetoh L, Ghiringhelli F. Th9 cells: a novel CD4 T-cell subset in the immune war against cancer. Cancer Res 2015; 75(3):475-9.
38. Deng Y, Wang Z, Chang C, Lu L, Lau CS, Lu Q. Th9 cells and IL-9 in autoimmune disorders: Pathogenesis
and therapeutic potentials. Hum Immunol 2017; 78(2):120-8.
39. Jadali Z, Eslami MB. T cell immune responses in psoriasis. Iran J Allergy Asthma Immunol 2014; 13(4):220-30.
40. Vanaki E, Ataei M, Sanati MH, Mansouri P, Mahmoudi M, Jadali Z. Expression patterns of Th1/Th2 transcription factors in patients with guttate psoriasis. Acta Microbiol Immunol Hung 2013;60(2):163-74.
41. Mansouri M, Mansouri P, Raze AA, Jadali Z. The potential role of Th17 lymphocytes in patients with psoriasis. An Bras Dermatol 2018; 93(1):63-6.
42. Ma L, Xue HB, Guan XH, Shu CM, Zhang JH, Yu J. Possible pathogenic role of T helper type 9 cells and interleukin (IL)-9 in atopic dermatitis. Clin Exp Immunol 2014; 175(1):25-31.
43. Singh TP, Schön MP, Wallbrecht K, Gruber-Wackernagel A, Wang XJ, Wolf P. Involvement of IL-9 in Th17-associated inflammation and angiogenesis of psoriasis. PLoS One 2013; 8(1):e51752.
44. Hamza AM, Omar SS, Abo El-Wafa RA, Elatrash MJ. Expression levels of transcription factor PU.1 and interleukin-9 in atopic dermatitis and their relation to disease severity and eruption types. Int J Dermatol 2017; 56(5):534-9.
45. Noelle RJ, Nowak EC. Cellular sources and immune functions of interleukin-9. Nat Rev Immunol 2010; 10(10): 683–7.
46. Zhao P, Xiao X, Ghobrial RM, Li XC. IL-9 and Th9 cells: progress and challenges. Int Immunol 2013; 25(10):547-51.
47. Kostner L, Anzengruber F, Guillod C, Recher M, Schmid-Grendelmeier P, Navarini AA. Allergic Contact Dermatitis. Immunol Allergy Clin North Am 2017; 37(1):141-52.
48. Rundle CW, Bergman D, Goldenberg A, Jacob SE. Contact dermatitis considerations in atopic dermatitis. Clin Dermatol 2017; 35(4):367-74.
49. Bechara R, Antonios D, Azouri H, Pallardy M. Nickel Sulfate Promotes IL-17A Producing CD4+ T Cells by an IL-23-Dependent Mechanism Regulated by TLR4 and Jak-STAT Pathways. J Invest Dermatol 2017; 137(10):2140-8.
50. Chen C, Liu X, Li Y, Liang H, Li K, Li J et al. Effects of Acupuncture on 1-chloro-2,4-dinitrochlorobenzene-induced Allergic Contact Dermatitis in Mice. J Acupunct Meridian Stud 2017; 10(4):252-60.
51. Liu J, Harberts E, Tammaro A, Girardi N, Filler RB, Fishelevich R et al. IL-9 regulates allergen-specific Th1 responses in allergic contact dermatitis. J Invest Dermatol 2014;134(7):1903-11.
52. Gutin L, Tammaro A, Fishelevich R, Gaspari AA. Elevation of IL-9 in Extreme Patch Test Reactions Suggests It Is an Inflammatory Mediator in Allergic Contact Dermatitis. Dermatitis 2016; 27(1):35-6.
53. Cortelazzi C, Campanini N, Ricci R, De Panfilis G. Inflammed skin harbours Th9 cells. Acta Derm Venereol 2013; 93(2):183-5.
54. Tumes DJ, Papadopoulos M, Endo Y, Onodera A, Hirahara K, Nakayama T. Epigenetic regulation of T-helper cell differentiation, memory, and plasticity in allergic asthma. Immunol Rev 2017; 278(1):8-19.
55. Rojas-Zuleta WG, Sanchez E. IL-9: Function, Sources, and Detection. Methods Mol Biol 2017; 1585:21-35 .
56. Li J, Chen S, Xiao X, Zhao Y, Ding W, Li XC. IL-9 and Th9 cells in health and diseases-From tolerance to immunopathology. Cytokine Growth Factor Rev 2017; 37:47-55.
57. Otsuka A, Nomura T, Rerknimitr P, Seidel JA, Honda T, Kabashima K. The interplay between genetic and environmental factors in the pathogenesis of atopic dermatitis. Immunol Rev 2017; 278(1):246-62.
58. Brunner PM, Guttman-Yassky E, Leung DY. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol 2017; 139(4S):S65-S76.
59. Ciprandi G, De Amici M, Giunta V, Marseglia A, Marseglia G. Serum interleukin-9 levels are associated with clinical severity in children with atopic dermatitis. Pediatr Dermatol 2013; 30(2):222-5.
60. Namkung JH, Lee JE, Kim E, Park GT, Yang HS, Jang HY et al. An association between IL-9 and IL-9 receptor gene polymorphisms and atopic dermatitis in a Korean population. J Dermatol Sci 2011; 62(1):16-21.
61. Suárez-Fariñas M, Dhingra N, Gittler J, Shemer A, Cardinale I, de Guzman Strong C et al. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin Immunol 2013; 132(2):361-70.
62. Diepgen TL; Early Treatment of the Atopic Child Study Group. Long-term treatment with cetirizine of infants with atopic dermatitis: a multi-country, double-blind, randomized, placebo-controlled trial (the ETAC trial) over 18 months. Pediatr Allergy Immunol 2002; 13(4):278-86.
63. Fasce L, Ciprandi G, Pronzato C, Cozzani S, Tosca MA, Grimaldi I et al. Cetirizine reduces ICAM-I on epithelial cells during nasal minimal persistent inflammation in asymptomatic children with mite-allergic asthma. Int Arch Allergy Immunol 1996; 109(3):272-6.
64. Saeki M, Kaminuma O, Nishimura T, Kitamura N, Mori A, Hiroi T. Th9 cells induce steroid-resistant bronchial hyperresponsiveness in mice. Allergol Int 2017; 66S:S35-40.
65. Louahed J, Zhou Y, Maloy WL, Rani PU, Weiss C, Tomer Y et al. Interleukin 9 promotes influx and local maturation of eosinophils. Blood 2001; 97(4):1035-42.
66. Gounni AS, Gregory B, Nutku E, Aris F, Latifa K, Minshall E et al. Interleukin-9 enhances interleukin-5 receptor expression, differentiation, and survival of human eosinophils. Blood 2000; 96(6):2163-71.
67. Yao W, Zhang Y, Jabeen R, Nguyen ET, Wilkes DS, Tepper RS et al. Interleukin-9 is required for allergic airway inflammation mediated by the cytokine TSLP. Immunity 2013; 38(2):360-72.
68. Koch S, Sopel N, Finotto S. Th9 and other IL-9-producing cells in allergic asthma. Semin Immunopathol 2017; 39(1):55-68.
69. Goswami R, Kaplan MH. A brief history of IL-9. J Immunol 2011; 186(6):3283-8.
70. Yanaba K, Yoshizaki A, Asano Y, Kadono T, Sato S. Serum interleukin 9 levels are increased in patients with systemic sclerosis: association with lower frequency and severity of pulmonary fibrosis. J Rheumatol 2011; 38(10):2193-7.
71. Radonjic-Hoesli S, Hofmeier KS, Micaletto S, Schmid-Grendelmeier P, Bircher A, Simon D. Urticaria and Angioedema: an Update on Classification and Pathogenesis. Clin Rev Allergy Immunol 2018; 54(1):88-101
72. Greaves MW. Pathology and classification of urticaria. Immunol Allergy Clin North Am 2014; 34(1):1-9.
73. Honda T, Nomura T, Kabashima K. Advances in atopic dermatitis and urticarial in 2016. J Allergy Clin Immunol. 2017 Aug;140(2):369-376.
74. Auyeung P, Mittag D, Hodgkin PD, Harrison LC. Autoreactive T cells in chronic spontaneous urticaria target the IgE Fc receptor Iα subunit. J Allergy Clin Immunol 2016; 138(3):761-8.
75. Zheng R, Qian L, Yu J, Li M, Qian Q. Analysis of the changes in Th9 cells and related cytokines in the peripheral blood of spontaneous urticaria patients. Biomed Rep 2017; 6(6):633-9.
76. Sehra S, Yao W, Nguyen ET, Glosson-Byers NL, Akhtar N, Zhou B et al. TH9 cells are required for tissue mast cell accumulation during allergic inflammation. J Allergy Clin Immunol 2015; 136(2):433-40.
77. Kay AB, Ying S, Ardelean E, Mlynek A, Kita H, Clark P et al. Elevations in vascular markers and eosinophils in chronic spontaneous urticarial weals with low-level persistence in uninvolved skin. Br J Dermatol 2014; 171(3):505-11.
78. Rojas-Zuleta WG, Vásquez G. Th9 lymphocytes: a recent history from IL-9 to its potential role in rheumatic diseases. Autoimmun Rev 2016; 15(7):649-55
79. Kaplan MH. Th9 cells: differentiation and disease. Immunol Rev 2013; 252(1):104-15.
80. Ciprandi G, De Amici M, Legoratto S, Giunta V, Vignini M, Borroni G. Serum IL-9 levels in patients with spontaneous urticaria: a preliminary study. J Investig Allergol Clin Immunol 2012; 22(3):232-4.
81. Metz M, Krull C, Maurer M. Histamine, TNF, C5a, IL-6, -9, -18, -31, -33, TSLP, neopterin, and VEGF are not elevated in chronic spontaneous urticaria. J Dermatol Sci 2013; 70(3):222-5.
82. Maurer M, Weller K, Bindslev-Jensen C, Giménez-Arnau A, Bousquet PJ, Bousquet J et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy 2011; 66(3):317-30.
83. Leru P. Urticaria--an allergologic, dermatologic or multidisciplinary disease? Rom J Intern Med 2013; 51(3-4):125-30.
84. Fine LM, Bernstein JA. Urticaria Guidelines: Consensus and Controversies in the European and American Guidelines. Curr Allergy Asthma Rep 2015; 15(6):30.