Treg expression of CIS suppresses allergic airway inflammation through antagonizing an autonomous TH2 program.

FULLTEXT
Published:
11.30.2019
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Last Revised:
04.15.2020
PMID:
31780776
Mucosal immunology
Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't
Authors:
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.,Department of Parasitology, School of Basic Medical Sciences, Xiangya School of Medicine, Central South University, Changsha, China.
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.,Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.,College of Agronomy, Hunan Agricultural University, Changsha, Hunan, 410128, China.
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.,Department of Parasitology, School of Basic Medical Sciences, Xiangya School of Medicine, Central South University, Changsha, China.
Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.,Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.
Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.
Institute of Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China.
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA. xyang@salud.unm.edu.

Abstract

Maintenance of regulatory T (Treg) cells is crucial for the regulatory function of Treg cells in immune homeostasis and self-tolerance; however, the detailed underlying mechanisms remain elusive. In the current study, we found that the cytokine suppressor CIS (cytokine induced SH-2 protein) is required for maintenance of Treg cell identity. Mice with Treg-specific Cis-deficiency displayed aggravated experimental allergic asthma, and in adulthood, developed splenomegaly, lymphadenopathy and spontaneous eosinophilic airway inflammation, accompanied by accumulation of effector memory helper T (TH) cells. Cis-deficiency led to the loss of Foxp3 expression and the decrease in suppressive function of Treg cells. Cis-deficient Treg cells expressed TH2 cell signature genes, Gata3, Irf4 and Il4, and excessive interleukin-4-signal transducer and activator of transcription 6 (IL-4-STAT6) signals resulted in repressive chromatin modification in the Foxp3 locus and permissive modification in the Il4 loci. In vitro, blockade of IL-4 restored the expression of Foxp3 and the suppressive function of inducible Treg (iTreg) cells. Thus, we identified a novel feedback loop in stabilization of Treg cells and suppression of TH2-type inflammation in a Treg-intrinsic manner.

GrantID: P30 CA118100, Acronym: CA, Agency: NCI NIH HHS, Country: United States | GrantID: R21 AI142200, Acronym: AI, Agency: NIAID NIH HHS, Country: United States | GrantID: P20 GM121176, Acronym: GM, Agency: NIGMS NIH HHS, Country: United States | GrantID: R01 DK110439, Acronym: DK, Agency: NIDDK NIH HHS, Country: United States | GrantID: R56 AI116772, Acronym: AI, Agency: NIAID NIH HHS, Country: United States