The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells

Shigeru Iwata, Yohei Mikami, Hong Wei Sun, Stephen R. Brooks, Dragana Jankovic, Kiyoshi Hirahara, Atsushi Onodera, Han Yu Shih, Takeshi Kawabe, Kan Jiang, Toshinori Nakayama, Alan Sher, John J. O'Shea, Fred P. Davis, Yuka Kanno

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

Host defense requires the specification of CD4+ helper T (Th) cells into distinct fates, including Th1 cells that preferentially produce interferon-γ (IFN-γ). IFN-γ, a member of a large family of anti-pathogenic and anti-tumor IFNs, induces T-bet, a lineage-defining transcription factor for Th1 cells, which in turn supports IFN-γ production in a feed-forward manner. Herein, we show that a cell-intrinsic role of T-bet influences how T cells perceive their secreted product in the environment. In the absence of T-bet, IFN-γ aberrantly induced a type I IFN transcriptomic program. T-bet preferentially repressed genes and pathways ordinarily activated by type I IFNs to ensure that its transcriptional response did not evoke an aberrant amplification of type I IFN signaling circuitry, otherwise triggered by its own product. Thus, in addition to promoting Th1 effector commitment, T-bet acts as a repressor in differentiated Th1 cells to prevent abberant autocrine type I IFN and downstream signaling. T-bet directs T helper 1 cell differentiation and IFN-γ production. Iwata et al. find that T-bet also acts as a repressor of type I IFN transcription factors and type-I-IFN-stimulated genes and collectively restrains IFN-γ-induced collateral type I IFN circuitry during the Th1 response.

Original languageEnglish
Pages (from-to)983-991.e4
JournalImmunity
Volume46
Issue number6
DOIs
Publication statusPublished - 2017 Jun 20

Keywords

  • ChIP-seq
  • JAK-STAT pathway
  • RNA-seq
  • STAT
  • T helper cells
  • T-bet
  • immunoregulation
  • interferon gamma
  • signal transducer and activator of transcription
  • transcription
  • type I interferons

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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