BATF2 inhibits immunopathological Th17 responses by suppressing Il23a expression during Trypanosoma cruzi infection

Shoko Kitada; Hisako Kayama; Daisuke Okuzaki; Ritsuko Koga; Masao Kobayashi; Yasunobu Arima; Atsushi Kumanogoh; Masaaki Murakami; Masahito Ikawa; Kiyoshi Takeda

doi:10.1084/jem.20161076

BATF2 inhibits immunopathological Th17 responses by suppressing Il23a expression during Trypanosoma cruzi infection

J Exp Med. 2017 May 1;214(5):1313-1331. doi: 10.1084/jem.20161076. Epub 2017 Mar 29.

Authors

Shoko Kitada^{1

2

3}, Hisako Kayama^{1

2

3}, Daisuke Okuzaki⁴, Ritsuko Koga⁵, Masao Kobayashi¹, Yasunobu Arima⁶, Atsushi Kumanogoh⁷, Masaaki Murakami⁶, Masahito Ikawa⁸, Kiyoshi Takeda^{9

2

3}

Affiliations

¹ Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
² WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
³ Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.
⁴ DNA-Chip Developmental Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
⁵ Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
⁶ Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
⁷ Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
⁸ Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
⁹ Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan ktakeda@ongene.med.osaka-u.ac.jp.

Abstract

Inappropriate IL-17 responses are implicated in chronic tissue inflammation. IL-23 contributes to Trypanosoma cruzi-specific IL-17 production, but the molecular mechanisms underlying regulation of the IL-23-IL-17 axis during T. cruzi infection are poorly understood. Here, we demonstrate a novel function of BATF2 as a negative regulator of Il23a in innate immune cells. IL-17, but not IFN-γ, was more highly produced by CD4⁺ T cells from spleens and livers of T. cruzi-infected Batf2^-/- mice than by those of wild-type mice. In this context, Batf2^-/- mice showed severe multiorgan pathology despite reduced parasite burden. T. cruzi-induced IL-23 production was increased in Batf2^-/- innate immune cells. The T. cruzi-induced enhanced Th17 response was abrogated in Batf2^-/-Il23a^-/- mice. The interaction of BATF2 with c-JUN prevented c-JUN-ATF-2 complex formation, inhibiting Il23a expression. These results demonstrate that IFN-γ-inducible BATF2 in innate immune cells controls Th17-mediated immunopathology by suppressing IL-23 production during T. cruzi infection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic-Leucine Zipper Transcription Factors / physiology*
Chagas Disease / immunology*
Chagas Disease / pathology
Female
Immunity, Innate / immunology
Interleukin-23 Subunit p19 / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Proto-Oncogene Proteins c-jun / physiology
Th17 Cells / immunology
Th17 Cells / physiology*
Trypanosoma cruzi / immunology*

Substances

BATF2 protein, mouse
Basic-Leucine Zipper Transcription Factors
Il23a protein, mouse
Interleukin-23 Subunit p19
Proto-Oncogene Proteins c-jun