title: IL-7 signalling represses Bcl-6 and the TFH gene program.
abstract: The transcriptional repressor Bcl-6 is linked to the development of both CD4(+) T follicular helper (TFH) and central memory T (TCM) cells. Here, we demonstrate that in response to decreased IL-2 signalling, T helper 1 (TH1) cells upregulate Bcl-6 and co-initiate TFH- and TCM-like gene programs, including expression of the cytokine receptors IL-6Rα and IL-7R. Exposure of this potentially bi-potent cell population to IL-6 favours the TFH gene program, whereas IL-7 signalling represses TFH-associated genes including Bcl6 and Cxcr5, but not the TCM-related genes Klf2 and Sell. Mechanistically, IL-7-dependent activation of STAT5 contributes to Bcl-6 repression. Importantly, antigen-specific IL-6Rα(+)IL-7R(+) CD4(+) T cells emerge from the effector population at late time points post influenza infection. These data support a novel role for IL-7 in the repression of the TFH gene program and evoke a divergent regulatory mechanism by which post-effector TH1 cells may contribute to long-term cell-mediated and humoral immunity.
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia 24016, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: McDonald
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia 24016, USA.
authors.forename: Kaitlin A
authors.initials: KA
authors.lastname: Read
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia 24016, USA.
authors.forename: Chandra E
authors.initials: CE
authors.lastname: Baker
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia 24016, USA.
authors.forename: Ashlyn E
authors.initials: AE
authors.lastname: Anderson
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia 24016, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Powell
authors.forename: André
authors.initials: A
authors.lastname: Ballesteros-Tato
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia 24016, USA.|Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia 24061, USA.|Virginia Tech Carilion School of Medicine, Roanoke, Virginia 24016, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Oestreich
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D015151:Immunoblotting; D007376:Interleukin-2 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D015851:Interleukin-7 / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D019041:L-Selectin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009976:Orthomyxoviridae Infections; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D054380:Receptors, CXCR5 / Q000235:genetics / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C490010:Bcl6 protein, mouse; C513179:CXCR5 protein, mouse; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D015850:Interleukin-6; D015851:Interleukin-7; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; C513258:Prdm1 protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D054380:Receptors, CXCR5; D019947:Receptors, Interleukin-6; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; D019041:L-Selectin; D000074462:Positive Regulatory Domain I-Binding Factor 1