title: Early Th1 cell differentiation is marked by a Tfh cell-like transition.
abstract: Follicular helper T (Tfh) cells comprise an important subset of helper T cells; however, their relationship with other helper lineages is incompletely understood. Herein, we showed interleukin-12 acting via the transcription factor STAT4 induced both Il21 and Bcl6 genes, generating cells with features of both Tfh and Th1 cells. However, STAT4 also induced the transcription factor T-bet. With ChIP-seq, we defined the genome-wide targets of T-bet and found that it repressed Bcl6 and other markers of Tfh cells, thereby attenuating the nascent Tfh cell-like phenotype in the late phase of Th1 cell specification. Tfh-like cells were rapidly generated after Toxoplasma gondii infection in mice, but T-bet constrained Tfh cell expansion and consequent germinal center formation and antibody production. Our data argue that Tfh and Th1 cells share a transitional stage through the signal mediated by STAT4, which promotes both phenotypes. However, T-bet represses Tfh cell functionalities, promoting full Th1 cell differentiation.
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. nakayamadas@mail.nih.gov
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakayamada
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kanno
authors.forename: Hayato
authors.initials: H
authors.lastname: Takahashi
authors.forename: Dragana
authors.initials: D
authors.lastname: Jankovic
authors.forename: Kristina T
authors.initials: KT
authors.lastname: Lu
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Johnson
authors.forename: Hong-wei
authors.initials: HW
authors.lastname: Sun
authors.forename: Golnaz
authors.initials: G
authors.lastname: Vahedi
authors.forename: Ofir
authors.initials: O
authors.lastname: Hakim
authors.forename: Robin
authors.initials: R
authors.lastname: Handon
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Schwartzberg
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Hager
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051560:Proto-Oncogene Proteins c-bcl-6; D050797:STAT4 Transcription Factor / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D014122:Toxoplasma; D000098815:T-bet Transcription Factor
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D050797:STAT4 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma