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C-Maf-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont

ABSTRACT: Both microbial and host genetic factors contribute to the pathogenesis of autoimmune disease. Accumulating evidence suggests that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease (IBD), often also colonize healthy individuals. These microbes, including the Helicobacter species, have the propensity to induce pathogenic T cells and are collectively referred to as pathobionts. However, an understanding of how such T cells are constrained in healthy individuals is lacking. For this study we wanted to compare the transcriptomes of H. hepaticus-specific T effector cells from mice that were IL-10-deficient to those that were Maf-deficient in the Treg compartment to determine if they share an inflammatory signature. We also compared Maf -sufficient and -deficient polyclonal iTreg to determine molecular targets of the TF c-Maf.

ORGANISM(S): Mus musculus

PROVIDER: GSE108184 | GEO | 2017/12/19

SECONDARY ACCESSION(S): PRJNA422768

REPOSITORIES: GEO

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Project description:The mutualistic relationship of gut-resident microbiota and cells of the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a poised, but largely non-aggressive, immune cell compartment1,2. Consequences of disturbing this balance, by environmental or genetic factors, include proximal inflammatory conditions, like Crohn’s disease, and systemic illnesses, both metabolic and autoimmune. One of the means by which this equilibrium is achieved is through induction of both effector and suppressor or regulatory arms of the adaptive immune system. In mice, Helicobacter species induce regulatory (iTreg) and follicular helper (Tfh) T cells in the colon-draining mesenteric lymph nodes under homeostatic conditions, but can instead induce inflammatory Th17 cells and colitis when iTreg cells are compromised3,4. How Helicobacter hepaticus and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. It could involve targeting a common antigen presenting cell (APC) by distinct microbial products, endowing it with specialized functions, or targeting APCs with pre-determined features suited to directing appropriate T cell differentiation programs. Here, we investigated which cells and molecular components are required to convey the microbial instruction for the iTreg differentiation program. We found that antigen presentation by cells expressing RORgt, rather than by classical dendritic cells, was both required and sufficient for iTreg induction. The MHC class II antigen presentation machinery, chemokine receptor CCR7, and av integrin, which activates TGF-β, were necessary in RORgt+ cells, likely type 3 innate lymphoid cells (ILC3), for iTreg cell differentiation. In the absence of any of these, instead of iTreg cells there was expansion of H. hepaticus-specific pathogenic Th17 cells, which were induced by other APCs that did not require CCR7. Our results illustrate the ability of microbiota to exploit specialized functions of distinct innate immune system cells, targeting them to achieve the desired composition of equipoised T cells, thus maintaining tolerance.

Project description:The mutualistic relationship of gut-resident microbiota and cells of the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a poised, but largely non-aggressive, immune cell compartment1. Consequences of disturbing this balance, by environmental or genetic factors, include proximal inflammatory conditions, like Crohn’s disease, and systemic illnesses, both metabolic and autoimmune. One of the means by which this equilibrium is achieved is through induction of both effector and suppressor or regulatory arms of the adaptive immune system. In mice, Helicobacter species induce regulatory (iTreg) and follicular helper (Tfh) T cells in the colon-draining mesenteric lymph nodes under homeostatic conditions, but can instead induce inflammatory Th17 cells when iTreg cells are compromised3,4. How Helicobacter hepaticus and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here, we investigated which cells and molecular components are required to convey the microbial instruction for the iTreg differentiation program. We found that antigen presentation by cells expressing RORgt, rather than by classical dendritic cells, was both required and sufficient for iTreg induction. These RORgt+ cells, likely to be type 3 innate lymphoid cells (ILC3) or a recently-described population of Aire+ cells termed Janus cells5, require the MHC class II antigen presentation machinery, the chemokine receptor CCR7, and av integrin, which activates TGF-β, for iTreg cell differentiation. In the absence of any of these, instead of iTreg cells there was expansion of microbiota-specific pathogenic Th17 cells, which were induced by other antigen presenting cells (APCs) that did not require CCR7. Thus, intestinal commensal microbes and their products target multiple APCs with pre-determined features suited to directing appropriate T cell differentiation programs, rather than a common APC that they endow with appropriate functions.

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C-Maf-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont

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