Background Th9 cells are a subset of CD4+ T cells that express the protoypical cytokine, IL-9. Th9 cells are known to effect protective immunity in animal models of intestinal helminth infections. However, the role of Th9 cells in human intestinal helminth infections has never been examined. Methodology To examine the role of Th9 cells in Strongyloidis stercoralis (Ss), a common intestinal helminth infection, we compared the frequency of Th9 expressing IL-9 either singly (mono-functional) or co-expressing IL-4 or IL-10 (dual-functional) in Ss-infected individuals (INF) to frequencies in uninfected (UN) individuals. Principal Findings INF individuals exhibited a significant increase in the spontaneously expressed and/or antigen specific frequencies of both mono- and dual-functional Th9 cells as well as Th2 cells expressing IL-9 compared to UN. The differences in Th9 induction between INF and UN individuals was predominantly antigen-specific as the differences were no longer seen following control antigen or mitogen stimulation. In addition, the increased frequency of Th9 cells in response to parasite antigens was dependent on IL-10 and TGFx since neutralization of either of these cytokines resulted in diminished Th9 frequencies. Finally, following successful treatment of Ss infection, the frequencies of antigen-specific Th9 cells diminished in INF individuals, suggesting a role for the Th9 response in active Ss infection. Moreover, IL-9 levels in whole blood culture supernatants following Ss antigen stimulation were higher in INF compared to UN individuals. Conclusion Thus, Ss infection is characterized by an IL-10- and TGFβ dependent expansion of Th9 cells, an expansion found to reversible by anti-helmintic treatment.
References
[1]
O'Shea JJ, Paul WE (2010) Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327: 1098–1102. doi: 10.1126/science.1178334. pmid:20185720
[2]
Noelle RJ, Nowak EC Cellular sources and immune functions of interleukin-9. Nat Rev Immunol 10: 683–687. doi: 10.1038/nri2848. pmid:20847745
[3]
Wilhelm C, Turner JE, Van Snick J, Stockinger B The many lives of IL-9: a question of survival? Nat Immunol 13: 637–641. doi: 10.1038/ni.2303. pmid:22713829
[4]
Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, et al. (2008) 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. doi: 10.1038/ni.1677. pmid:18997793
[5]
Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, et al. (2008) Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9: 1341–1346. doi: 10.1038/ni.1659. pmid:18931678
Kaplan MH, Hufford MM, Olson MR (2015) The development and in vivo function of T helper 9 cells. Nat Rev Immunol 15: 295–307. doi: 10.1038/nri3824. pmid:25848755
[8]
Beriou G, Bradshaw EM, Lozano E, Costantino CM, Hastings WD, et al. TGF-beta induces IL-9 production from human Th17 cells. J Immunol 185: 46–54. doi: 10.4049/jimmunol.1000356. pmid:20498357
[9]
Jones CP, Gregory LG, Causton B, Campbell GA, Lloyd CM (2012) Activin A and TGF-beta promote T(H)9 cell-mediated pulmonary allergic pathology. J Allergy Clin Immunol 129: 1000–1010 e1003. doi: 10.1016/j.jaci.2011.12.965. pmid:22277204
[10]
Yao W, Zhang Y, Jabeen R, Nguyen ET, Wilkes DS, et al. (2013) Interleukin-9 is required for allergic airway inflammation mediated by the cytokine TSLP. Immunity 38: 360–372. doi: 10.1016/j.immuni.2013.01.007. pmid:23376058
[11]
Purwar R, Schlapbach C, Xiao S, Kang HS, Elyaman W, et al. (2012) Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 18: 1248–1253. doi: 10.1038/nm.2856. pmid:22772464
[12]
Soroosh P, Doherty TA (2009) Th9 and allergic disease. Immunology 127: 450–458. doi: 10.1111/j.1365-2567.2009.03114.x. pmid:19604299
[13]
Yao W, Tepper RS, Kaplan MH (2011) Predisposition to the development of IL-9-secreting T cells in atopic infants. J Allergy Clin Immunol 128: 1357–1360 e1355. doi: 10.1016/j.jaci.2011.06.019. pmid:21798577
[14]
Pan HF, Leng RX, Li XP, Zheng SG, Ye DQ (2013) Targeting T-helper 9 cells and interleukin-9 in autoimmune diseases. Cytokine Growth Factor Rev 24: 515–522. pmid:25215394 doi: 10.1016/j.cytogfr.2013.09.001
[15]
Faulkner H, Humphreys N, Renauld JC, Van Snick J, Grencis R (1997) Interleukin-9 is involved in host protective immunity to intestinal nematode infection. Eur J Immunol 27: 2536–2540. pmid:9368607 doi: 10.1002/eji.1830271011
[16]
Faulkner H, Renauld JC, Van Snick J, Grencis RK (1998) Interleukin-9 enhances resistance to the intestinal nematode Trichuris muris. Infect Immun 66: 3832–3840. pmid:9673269
[17]
Richard M, Grencis RK, Humphreys NE, Renauld JC, Van Snick J (2000) Anti-IL-9 vaccination prevents worm expulsion and blood eosinophilia in Trichuris muris-infected mice. Proc Natl Acad Sci U S A 97: 767–772. pmid:10639154 doi: 10.1073/pnas.97.2.767
[18]
Montes M, Sanchez C, Verdonck K, Lake JE, Gonzalez E, et al. (2009) Regulatory T cell expansion in HTLV-1 and strongyloidiasis co-infection is associated with reduced IL-5 responses to Strongyloides stercoralis antigen. PLoS Negl Trop Dis 3: e456. doi: 10.1371/journal.pntd.0000456. pmid:19513105
[19]
Neva FA, Filho JO, Gam AA, Thompson R, Freitas V, et al. (1998) Interferon-gamma and interleukin-4 responses in relation to serum IgE levels in persons infected with human T lymphotropic virus type I and Strongyloides stercoralis. J Infect Dis 178: 1856–1859. pmid:9815251 doi: 10.1086/314507
[20]
Porto AF, Neva FA, Bittencourt H, Lisboa W, Thompson R, et al. (2001) HTLV-1 decreases Th2 type of immune response in patients with strongyloidiasis. Parasite Immunol 23: 503–507. pmid:11589779 doi: 10.1046/j.1365-3024.2001.00407.x
[21]
Rotman HL, Schnyder-Candrian S, Scott P, Nolan TJ, Schad GA, et al. (1997) IL-12 eliminates the Th-2 dependent protective immune response of mice to larval Strongyloides stercoralis. Parasite Immunol 19: 29–39. pmid:9121838 doi: 10.1046/j.1365-3024.1997.d01-142.x
[22]
Bonne-Annee S, Hess JA, Abraham D (2011) Innate and adaptive immunity to the nematode Strongyloides stercoralis in a mouse model. Immunol Res 51: 205–214. doi: 10.1007/s12026-011-8258-2. pmid:22101674
[23]
Anuradha R, Munisankar S, Dolla C, Kumaran P, Nutman TB, et al. (2015) Parasite Antigen-Specific Regulation of Th1, Th2, and Th17 Responses in Strongyloides stercoralis Infection. J Immunol 195: 2241–2250. doi: 10.4049/jimmunol.1500745. pmid:26202988
[24]
Ramanathan R, Burbelo PD, Groot S, Iadarola MJ, Neva FA, et al. (2008) A luciferase immunoprecipitation systems assay enhances the sensitivity and specificity of diagnosis of Strongyloides stercoralis infection. J Infect Dis 198: 444–451. doi: 10.1086/589718. pmid:18558872
[25]
Licona-Limon P, Henao-Mejia J, Temann AU, Gagliani N, Licona-Limon I, et al. (2013) Th9 Cells Drive Host Immunity against Gastrointestinal Worm Infection. Immunity 39: 744–757. doi: 10.1016/j.immuni.2013.07.020. pmid:24138883
[26]
Goswami R, Kaplan MH (2011) A brief history of IL-9. J Immunol 186: 3283–3288. doi: 10.4049/jimmunol.1003049. pmid:21368237
[27]
Uyttenhove C, Simpson RJ, Van Snick J (1988) Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity. Proc Natl Acad Sci U S A 85: 6934–6938. pmid:3137580 doi: 10.1073/pnas.85.18.6934
[28]
Van Snick J, Goethals A, Renauld JC, Van Roost E, Uyttenhove C, et al. (1989) Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40). J Exp Med 169: 363–368. pmid:2521242 doi: 10.1084/jem.169.1.363
[29]
Petit-Frere C, Dugas B, Braquet P, Mencia-Huerta JM (1993) Interleukin-9 potentiates the interleukin-4-induced IgE and IgG1 release from murine B lymphocytes. Immunology 79: 146–151. pmid:8509135 doi: 10.1002/eji.1830230743
[30]
Dong Q, Louahed J, Vink A, Sullivan CD, Messler CJ, et al. (1999) IL-9 induces chemokine expression in lung epithelial cells and baseline airway eosinophilia in transgenic mice. Eur J Immunol 29: 2130–2139. pmid:10427975 doi: 10.1002/(sici)1521-4141(199907)29:07<2130::aid-immu2130>3.0.co;2-s
