title: The role of IL-15 in activating STAT5 and fine-tuning IL-17A production in CD4 T lymphocytes.
abstract: IL-15 is an important IL-2-related cytokine whose role in Th17 cell biology has not been fully elucidated. In this study, we show that exogenous IL-15 decreased IL-17A production in Th17 cultures. Neutralization of IL-15 using an Ab led to increases in IL-17A production in Th17 cultures. Both Il15(-/-) and Il15r(-/-) T cell cultures displayed higher frequency of IL-17A producers and higher amounts of IL-17A in the supernatants compared with those of wild-type (WT) cells in vitro. IL-15 down-modulated IL-17A production independently of retinoic acid-related orphan receptor-γt, Foxp3, and IFN-γ expression. Both Th17 cells and APCs produced IL-15, which induced binding of STAT5, an apparent repressor to the Il17 locus in CD4 T cells. Also, in a model of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE), Il15(-/-) mice displayed exacerbated inflammation-correlating with increased IL-17A production by their CD4(+) T cells-compared with WT controls. Exogenous IL-15 administration and IL-17A neutralization reduced the severity of EAE in Il15(-/-) mice. Taken together, these data indicate that IL-15 has a negative regulatory role in fine-tuning of IL-17A production and Th17-mediated inflammation.
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Pushpa
authors.initials: P
authors.lastname: Pandiyan
authors.forename: Xiang-Ping
authors.initials: XP
authors.lastname: Yang
authors.forename: Senthil S
authors.initials: SS
authors.lastname: Saravanamuthu
authors.forename: Lixin
authors.initials: L
authors.lastname: Zheng
authors.forename: Satoru
authors.initials: S
authors.lastname: Ishihara
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D019409:Interleukin-15 / Q000172:deficiency / Q000502:physiology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D019409:Interleukin-15; D020381:Interleukin-17; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse