NLRP6 deficiency expands a novel CD103 + B cell population that confers immune tolerance in NOD mice

Pearson, James A. ORCID: https://orcid.org/0000-0002-2867-2269, Peng, Jian, Huang, Juan, Yu, Xiaoqing, Tai, Ningwen, Hu, Youjia, Sha, Sha, Flavell, Richard A., Zhao, Hongyu, Wong, F. Susan ORCID: https://orcid.org/0000-0002-2812-8845 and Wen, Li 2023. NLRP6 deficiency expands a novel CD103 + B cell population that confers immune tolerance in NOD mice. Frontiers in Immunology 14 , 1147925. 10.3389/fimmu.2023.1147925

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Abstract

Introduction: Gut microbiota have been linked to modulating susceptibility to Type 1 diabetes; however, there are many ways in which the microbiota interact with host cells, including through microbial ligand binding to intracellular inflammasomes (large multi-subunit proteins) to initiate immune responses. NLRP6, a microbe-recognizing inflammasome protein, is highly expressed by intestinal epithelial cells and can alter susceptibility to cancer, obesity and Crohn’s disease; however, the role of NLRP6 in modulating susceptibility to autoimmune diabetes, was previously unknown. Methods: We generated NLRP6-deficient Non-obese diabetic (NOD) mice to study the effect of NLRP6-deficiency on the immune cells and susceptibility to Type 1 diabetes development. Results: NLRP6-deficient mice exhibited an expansion of CD103+ B cells and were protected from type 1 diabetes. Moreover, NLRP6-deficient CD103+ B cells express regulatory markers, secreted higher concentrations of IL-10 and TGFb1 cytokines and suppressed diabetogenic T cell proliferation, compared to NLRP6-sufficient CD103+ B cells. Microarray analysis of NLRP6-sufficient and -deficient CD103+ B cells identified 79 significantly different genes including genes regulated by lipopolysaccharide (LPS), tretinoin, IL-10 and TGFb, which was confirmed in vitro following LPS stimulation. Furthermore, microbiota from NLRP6-deficient mice induced CD103+ B cells in colonized NLRP6-sufficient germ-free mice; however, the long-term maintenance of the CD103+ B cells required the absence of NLRP6 in the hosts, or continued exposure to microbiota from NLRP6-deficient mice. Discussion: Together, our data indicate that NLRP6 deficiency promotes expansion and maintenance of a novel TGF -dependent CD103+ Breg population. Thus, targeting NLRP6 therapeutically may prove clinically useful.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Frontiers Media
Funders:	MRC
Date of First Compliant Deposit:	10 March 2023
Date of Acceptance:	6 February 2023
Last Modified:	19 Jun 2023 22:20
URI:	https://orca.cardiff.ac.uk/id/eprint/157637

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