Intestinal commensal microbiota and cytokines regulate Fut2+ Paneth cells for gut defense

Mariko Kamioka; Yoshiyuki Goto; Kiminori Nakamura; Yuki Yokoi; Rina Sugimoto; Shuya Ohira; Yosuke Kurashima; Shingo Umemoto; Shintaro Sato; Jun Kunisawa; Yu Takahashi; Steven E Domino; Jean-Christophe Renauld; Susumu Nakae; Yoichiro Iwakura; Peter B Ernst; Tokiyoshi Ayabe; Hiroshi Kiyono

doi:10.1073/pnas.2115230119

Intestinal commensal microbiota and cytokines regulate Fut2⁺ Paneth cells for gut defense

Proc Natl Acad Sci U S A. 2022 Jan 18;119(3):e2115230119. doi: 10.1073/pnas.2115230119.

Authors

Mariko Kamioka^{1

2

3

4}, Yoshiyuki Goto^{2

5}, Kiminori Nakamura⁶, Yuki Yokoi⁶, Rina Sugimoto⁶, Shuya Ohira⁶, Yosuke Kurashima^{1

2

3

4

7}, Shingo Umemoto^{1

3

8}, Shintaro Sato^{1

9

10}, Jun Kunisawa^{2

4}, Yu Takahashi¹¹, Steven E Domino¹², Jean-Christophe Renauld¹³, Susumu Nakae¹⁴, Yoichiro Iwakura¹⁵, Peter B Ernst^{3

16

17

18}, Tokiyoshi Ayabe⁶, Hiroshi Kiyono^{19

2

3

18}

Affiliations

¹ Department of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
² International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
³ Department of Medicine, School of Medicine and Chiba University-University of California San Diego Center for Mucosal Immunology, Allergy and Vaccine (CU-UCSD cMAV), University of California, San Diego, CA 92093.
⁴ Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health, and Nutrition, Osaka 567-0085, Japan.
⁵ Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan.
⁶ Department of Cell Biological Science, Graduate School of Life Science, Faculty of Advanced Life Science, Hokkaido University, Hokkaido 001-0021, Japan.
⁷ Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
⁸ Department of Otolaryngology and Head and Neck Surgery, Faculty of Medicine, Oita University, Oita 879-5593, Japan.
⁹ Mucosal Vaccine Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
¹⁰ Department of Immunology and Genomics, Osaka City University, Graduate School of Medicine, Osaka 545-8585, Japan.
¹¹ Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
¹² Department of Obstetrics and Gynecology, Cellular and Molecular Biology Program, University of Michigan Medical Center, Ann Arbor, MI 48109-5617.
¹³ Ludwig Institute for Cancer Research, Université Catholique de Louvain, Brussels B-1200, Belgium.
¹⁴ Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8528, Japan.
¹⁵ Center for Experimental Animal Models, Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.
¹⁶ Division of Comparative Pathology and Medicine, Department of Pathology, University of California, San Diego, CA 92093.
¹⁷ Center for Veterinary Sciences and Comparative Medicine, University of California, San Diego, CA 92093.
¹⁸ Future Medicine Education and Research Organization, Chiba University, Chiba 260-8670, Japan.
¹⁹ Department of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; kiyono@ims.u-tokyo.ac.jp.

Abstract

Paneth cells are intestinal epithelial cells that release antimicrobial peptides, such as α-defensin as part of host defense. Together with mesenchymal cells, Paneth cells provide niche factors for epithelial stem cell homeostasis. Here, we report two subtypes of murine Paneth cells, differentiated by their production and utilization of fucosyltransferase 2 (Fut2), which regulates α(1,2)fucosylation to create cohabitation niches for commensal bacteria and prevent invasion of the intestine by pathogenic bacteria. The majority of Fut2^- Paneth cells were localized in the duodenum, whereas the majority of Fut2⁺ Paneth cells were in the ileum. Fut2⁺ Paneth cells showed higher granularity and structural complexity than did Fut2^- Paneth cells, suggesting that Fut2⁺ Paneth cells are involved in host defense. Signaling by the commensal bacteria, together with interleukin 22 (IL-22), induced the development of Fut2⁺ Paneth cells. IL-22 was found to affect the α-defensin secretion system via modulation of Fut2 expression, and IL-17a was found to increase the production of α-defensin in the intestinal tract. Thus, these intestinal cytokines regulate the development and function of Fut2⁺ Paneth cells as part of gut defense.

Keywords: IL-17a; IL-22; Paneth cell; fucosyltransferase 2; α-defensin.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cytokines / metabolism*
Fucosyltransferases / genetics
Fucosyltransferases / metabolism*
Galactoside 2-alpha-L-fucosyltransferase
Gastrointestinal Microbiome / physiology*
Ileum
Interleukin-17 / metabolism
Interleukin-22
Interleukins / metabolism
Mice
Paneth Cells / metabolism*
Symbiosis
alpha-Defensins / metabolism

Substances

Cytokines
Il17a protein, mouse
Interleukin-17
Interleukins
alpha-Defensins
Fucosyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding