title: TGF-beta induces IL-9 production from human Th17 cells.
abstract: The secretion of IL-9, initially recognized as a Th2 cytokine, was recently attributed to a novel CD4 T cell subset termed Th9 in the murine system. However, IL-9 can also be secreted by mouse Th17 cells and may mediate aspects of the proinflammatory activities of Th17 cells. Here we report that IL-9 is secreted by human naive CD4 T cells in response to differentiation by Th9 (TGF-beta and IL-4) or Th17 polarizing conditions. Yet, these differentiated naive cells did not coexpress IL-17 and IL-9, unless they were repeatedly stimulated under Th17 differentiation-inducing conditions. In contrast to the naive cells, memory CD4 T cells were induced to secrete IL-9 by simply providing TGF-beta during stimulation, as neither IL-4 nor proinflammatory cytokines were required. Furthermore, the addition of TGF-beta to the Th17-inducing cytokines (IL-1beta, IL-6, IL-21, IL-23) that induce memory cells to secrete IL-17, resulted in the marked coexpression of IL-9 in IL-17 producing memory cells. The proinflammatory cytokine mediating TGF-beta-dependent coexpression of IL-9 and IL-17 was identified to be IL-1beta. Moreover, circulating monocytes were potent costimulators of IL-9 production by Th17 cells via their capacity to secrete IL-1beta. Finally, to determine whether IL-9/IL-17 coproducing CD4 cells were altered in an inflammatory condition, we examined patients with autoimmune diabetes and demonstrated that these subjects exhibit a higher frequency of memory CD4 cells with the capacity to transition into IL-9(+)IL-17(+) cells. These data demonstrate the presence of IL-17(+)IL-9(+) CD4 cells induced by IL-1beta that may play a role in human autoimmune disease.
authors.affiliation: Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Beriou
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Bradshaw
authors.forename: Ester
authors.initials: E
authors.lastname: Lozano
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Costantino
authors.forename: William D
authors.initials: WD
authors.lastname: Hastings
authors.forename: Tihamer
authors.initials: T
authors.lastname: Orban
authors.forename: Wassim
authors.initials: W
authors.lastname: Elyaman
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Clare
authors.initials: C
authors.lastname: Baecher-Allan
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
mesh_terms: D000328:Adult; D016764:Cell Polarity / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D020381:Interleukin-17 / Q000096:biosynthesis*; D016906:Interleukin-9 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D055815:Young Adult
chemical_list: C508717:IL17A protein, human; C508607:IL9 protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17; D016906:Interleukin-9; D053773:Transforming Growth Factor beta1