Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of TH17 cell immunity

Chia-Hao Lin; Cheng-Jang Wu; Sunglim Cho; Rasika Patkar; William J Huth; Ling-Li Lin; Mei-Chi Chen; Elisabeth Israelsson; Joanne Betts; Magdalena Niedzielska; Shefali A Patel; Han G Duong; Romana R Gerner; Chia-Yun Hsu; Matthew Catley; Rose A Maciewicz; Hiutung Chu; Manuela Raffatellu; John T Chang; Li-Fan Lu

doi:10.1038/s41590-023-01667-y

Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of T_H17 cell immunity

Nat Immunol. 2023 Dec;24(12):2108-2120. doi: 10.1038/s41590-023-01667-y. Epub 2023 Nov 6.

Authors

Chia-Hao Lin¹, Cheng-Jang Wu¹, Sunglim Cho¹, Rasika Patkar¹, William J Huth¹, Ling-Li Lin¹, Mei-Chi Chen¹, Elisabeth Israelsson², Joanne Betts², Magdalena Niedzielska³, Shefali A Patel⁴, Han G Duong⁴, Romana R Gerner⁵, Chia-Yun Hsu⁶, Matthew Catley³, Rose A Maciewicz³, Hiutung Chu^{6

7

8}, Manuela Raffatellu^{5

7

8}, John T Chang^{4

9}, Li-Fan Lu^{10

11

12}

Affiliations

¹ School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
² Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
³ Bioscience, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
⁴ Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
⁵ Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
⁶ Department of Pathology, University of California San Diego, La Jolla, CA, USA.
⁷ UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines, Chiba University, La Jolla, CA, USA.
⁸ Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA.
⁹ Department of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
¹⁰ School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA. [email protected].
¹¹ Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA. [email protected].
¹² Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. [email protected].

Abstract

Regulatory T cells (T_reg cells) are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which T_reg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying T_reg cells from different tissue origins under systemic autoimmunity, in the present study we show that interleukin (IL)-27 is specifically produced by intestinal T_reg cells to regulate helper T17 cell (T_H17 cell) immunity. Selectively increased intestinal T_H17 cell responses in mice with T_reg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83⁺CD62L^lo T_reg cell subset that is distinct from previously characterized intestinal T_reg cell populations as the main IL-27 producers. Collectively, our study uncovers a new T_reg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue and provides further mechanistic insights into tissue-specific T_reg cell-mediated immune regulation.

MeSH terms

Animals
Immune Tolerance
Immunity, Cellular
Interleukin-27*
Mice
T-Lymphocytes, Helper-Inducer
T-Lymphocytes, Regulatory*
Th17 Cells

Substances

Interleukin-27

Abstract

MeSH terms

Substances

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