Suppression of IL-17F, but not of IL-17A, provides protection against colitis by inducing Treg cells through modification of the intestinal microbiota

Ce Tang; Shigeru Kakuta; Kenji Shimizu; Motohiko Kadoki; Tomonori Kamiya; Tomoyuki Shimazu; Sachiko Kubo; Shinobu Saijo; Harumichi Ishigame; Susumu Nakae; Yoichiro Iwakura

doi:10.1038/s41590-018-0134-y

Suppression of IL-17F, but not of IL-17A, provides protection against colitis by inducing T_reg cells through modification of the intestinal microbiota

Nat Immunol. 2018 Jul;19(7):755-765. doi: 10.1038/s41590-018-0134-y. Epub 2018 Jun 18.

Authors

Ce Tang^{1

2}, Shigeru Kakuta^{2

3}, Kenji Shimizu^{1

2

4}, Motohiko Kadoki^{1

2

5}, Tomonori Kamiya^{1

2

6}, Tomoyuki Shimazu^{1

7}, Sachiko Kubo^{1

2}, Shinobu Saijo^{2

8}, Harumichi Ishigame^{2

9}, Susumu Nakae², Yoichiro Iwakura^{10

11}

Affiliations

¹ Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda-shi, Chiba, Japan.
² Center for Experimental Medicine and Systems Biology, Institute of Medical Science, the University of Tokyo, Minato-ku, Tokyo, Japan.
³ Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, the University of Tokyo, Bunkyo-ku, Tokyo, Japan.
⁴ Division of Immune Regulation, Institute for Genome Research, Tokushima University, Tokushima-shi, Tokushima, Japan.
⁵ Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.
⁶ Department of Pathophysiology, Graduate School of Medicine, Osaka City University, Osaka-shi, Osaka, Japan.
⁷ Department of Food, Agriculture and Environment, Miyagi University, Sendai-shi, Miyagi, Japan.
⁸ Medical Mycobiology Research Center, Chiba University, Chiba-shi, Chiba, Japan.
⁹ RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
¹⁰ Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda-shi, Chiba, Japan. [email protected].
¹¹ Center for Experimental Medicine and Systems Biology, Institute of Medical Science, the University of Tokyo, Minato-ku, Tokyo, Japan. [email protected].

PMID: 29915298
DOI: 10.1038/s41590-018-0134-y

Abstract

The cytokines IL-17A and IL-17F have 50% amino-acid identity and bind the same receptor; however, their functional differences have remained obscure. Here we found that Il17f^-/- mice resisted chemically induced colitis, but Il17a^-/- mice did not, and that Il17f^-/- CD45RB^hiCD4⁺ T cells induced milder colitis in lymphocyte-deficient Rag2^-/- mice, accompanied by an increase in intestinal regulatory T cells (T_reg cells). Clostridium cluster XIVa in colonic microbiota capable of inducing T_reg cells was increased in both Il17f^-/- mice and mice given transfer Il17f^-/- T cells, due to decreased expression of a group of antimicrobial proteins. There was substantial production of IL-17F, but not of IL-17A, not only by naive T cells but also by various colon-resident cells under physiological conditions. Furthermore, antibody to IL-17F suppressed the development of colitis, but antibody to IL-17A did not. These observations suggest that IL-17F is an effective target for the treatment of colitis.

Publication types

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

MeSH terms

Animals
Cells, Cultured
Clostridium / growth & development
Clostridium / isolation & purification
Colitis / drug therapy
Colitis / immunology*
Gastrointestinal Microbiome*
Interleukin-17 / antagonists & inhibitors*
Interleukin-17 / genetics
Interleukin-17 / physiology
Intestines / immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Phospholipases A2 / biosynthesis
Phospholipases A2 / genetics
Prevotella / isolation & purification
Ribonuclease, Pancreatic / biosynthesis
Ribonuclease, Pancreatic / genetics
T-Lymphocytes, Regulatory / immunology*
beta-Defensins / biosynthesis

Substances

Interleukin-17
beta-Defensins
Phospholipases A2
Ang4 protein, mouse
Ribonuclease, Pancreatic