title: Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression.
abstract: Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the cytokines IL-6 and TGF-β expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4(+) and CD8(+) T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-β-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to their promoters. Accordingly, Th17 cells differentiated with IL-1β, IL-6, and IL-23 but without TGF-β did not express ectonucleotidases and were not immunosuppressive. Finally, adoptive transfer of Th17 cells induced by TGF-β and IL-6 promoted tumor growth in a CD39-dependent manner. Thus, ectonucleotidase expression supports the immunosuppressive fate of Th17 cells in cancer.
authors.affiliation: INSERM, U866, 21000 Dijon, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Chalmin
authors.forename: Grégoire
authors.initials: G
authors.lastname: Mignot
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bruchard
authors.forename: Angélique
authors.initials: A
authors.lastname: Chevriaux
authors.forename: Frédérique
authors.initials: F
authors.lastname: Végran
authors.forename: Aziz
authors.initials: A
authors.lastname: Hichami
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ladoire
authors.forename: Valentin
authors.initials: V
authors.lastname: Derangère
authors.forename: Julie
authors.initials: J
authors.lastname: Vincent
authors.forename: David
authors.initials: D
authors.lastname: Masson
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Gerard
authors.initials: G
authors.lastname: Eberl
authors.forename: Jean René
authors.initials: JR
authors.lastname: Pallandre
authors.forename: Christophe
authors.initials: C
authors.lastname: Borg
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.forename: Cédric
authors.initials: C
authors.lastname: Rébé
authors.forename: Francois
authors.initials: F
authors.lastname: Ghiringhelli
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D001081:Apyrase / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D004268:DNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000494:pharmacology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; D015850:Interleukin-6; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen