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ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut.

ABSTRACT: Microbial colonization of the mammalian intestine elicits inflammatory or tolerogenic T cell responses, but the mechanisms controlling these distinct outcomes remain poorly understood, and accumulating evidence indicates that aberrant immunity to intestinal microbiota is causally associated with infectious, inflammatory and malignant diseases^1-8. Here we define a critical pathway controlling the fate of inflammatory versus tolerogenic T cells that respond to the microbiota and express the transcription factor RORγt. We profiled all RORγt⁺ immune cells at single-cell resolution from the intestine-draining lymph nodes of mice and reveal a dominant presence of T regulatory (T_reg) cells and lymphoid tissue inducer-like group 3 innate lymphoid cells (ILC3s), which co-localize at interfollicular regions. These ILC3s are distinct from extrathymic AIRE-expressing cells, abundantly express major histocompatibility complex class II, and are necessary and sufficient to promote microbiota-specific RORγt⁺ T_reg cells and prevent their expansion as inflammatory T helper 17 cells. This occurs through ILC3-mediated antigen presentation, αV integrin and competition for interleukin-2. Finally, single-cell analyses suggest that interactions between ILC3s and RORγt⁺ T_reg cells are impaired in inflammatory bowel disease. Our results define a paradigm whereby ILC3s select for antigen-specific RORγt⁺ T_reg cells, and against T helper 17 cells, to establish immune tolerance to the microbiota and intestinal health.

SUBMITTER: Lyu M

PROVIDER: S-EPMC9613541 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut.

Lyu Mengze M Suzuki Hiroaki H Kang Lan L Gaspal Fabrina F Zhou Wenqing W Goc Jeremy J Zhou Lei L Zhou Jordan J Zhang Wen W Shen Zeli Z Fox James G JG Sockolow Robbyn E RE Laufer Terri M TM Fan Yong Y Eberl Gerard G Withers David R DR Sonnenberg Gregory F GF

Nature 20220907 7933

Microbial colonization of the mammalian intestine elicits inflammatory or tolerogenic T cell responses, but the mechanisms controlling these distinct outcomes remain poorly understood, and accumulating evidence indicates that aberrant immunity to intestinal microbiota is causally associated with infectious, inflammatory and malignant diseases<sup>1-8</sup>. Here we define a critical pathway controlling the fate of inflammatory versus tolerogenic T cells that respond to the microbiota and express ...[more]

PMID: 36071169

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Project description:BackgroundShort-chain fatty acids derived from gut microbial fermentation of dietary fiber have been shown to suppress autoimmunity through mechanisms that include enhanced regulation by T regulatory cells (Tregs).MethodsUsing a murine kidney transplantation model, we examined the effects on alloimmunity of a high-fiber diet or supplementation with the short-chain fatty acid acetate. Kidney transplants were performed from BALB/c(H2d) to B6(H2b) mice as allografts in wild-type and recipient mice lacking the G protein-coupled receptor GPR43 (the metabolite-sensing receptor of acetate). Allograft mice received normal chow, a high-fiber diet, or normal chow supplemented with sodium acetate. We assessed rejection at days 14 (acute) and 100 (chronic), and used 16S rRNA sequencing to determine gut microbiota composition pretransplantation and post-transplantation.ResultsWild-type mice fed normal chow exhibited dysbiosis after receiving a kidney allograft but not an isograft, despite the avoidance of antibiotics and immunosuppression for the latter. A high-fiber diet prevented dysbiosis in allograft recipients, who demonstrated prolonged survival and reduced evidence of rejection compared with mice fed normal chow. Allograft mice receiving supplemental sodium acetate exhibited similar protection from rejection, and subsequently demonstrated donor-specific tolerance. Depletion of CD25+ Tregs or absence of the short-chain fatty acid receptor GPR43 abolished this survival advantage.ConclusionsManipulation of the microbiome by a high-fiber diet or supplementation with sodium acetate modified alloimmunity in a kidney transplant model, generating tolerance dependent on Tregs and GPR43. Diet-based therapy to induce changes in the gut microbiome can alter systemic alloimmunity in mice, in part through the production of short-chain fatty acids leading to Treg cell development, and merits study as a potential clinical strategy to facilitate transplant acceptance.

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ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut.

Publications

ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut.

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