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Immunity. 2017 Jun 20;46(6):983-991.e4. doi: 10.1016/j.immuni.2017.05.005. Epub 2017 Jun 13.

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

Author information

1
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
2
Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
3
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
4
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
5
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Institute for Global Prominent Research, Chiba University, Chiba 260-8670, Japan.
6
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Cytokine Biology Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
7
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; AMED-CREST, AMED, Chiba 260-8670, Japan.
8
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: john.oshea@nih.gov.
9
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: fred.davis@nih.gov.
10
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: kannoy@mail.nih.gov.

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.

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

Comment in

PMID:
28623086
PMCID:
PMC5523825
DOI:
10.1016/j.immuni.2017.05.005
[Indexed for MEDLINE]
Free PMC Article

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