Multiple sclerosis (MS) is a T cell-driven autoimmune disease that attacks the myelin of the central nervous system (CNS) and currently has no cure. MS etiology is linked to both the gut flora and external environmental factors but this connection is not well understood. One immune system regulator responsive to nonpathogenic external stimuli is the aryl hydrocarbon receptor (AHR). The AHR, which binds diverse molecules present in the environment in barrier tissues, is a therapeutic target for MS. However, AHR’s precise function in T lymphocytes, the orchestrators of MS, has not been described. Here, we show that in a mouse model of MS, T cell-specific Ahr knockout leads to recovery driven by a decrease in T cell fitness. At the mechanistic level, we demonstrate that the absence of AHR changes the gut microenvironment composition to generate metabolites that impact T cell viability, such as bile salts and short chain fatty acids. Our study demonstrates a newly emerging role for AHR in mediating the interdependence between T lymphocytes and the microbiota, while simultaneously identifying new potential molecular targets for the treatment of MS and other autoimmune diseases.

Multiple sclerosis (MS) is an incurable T cell driven autoimmune disease of the central nervous system. The contribution of the environment and, in particular, the gut flora to MS etiology is well documented but not well understood. The aryl hydrocarbon receptor (AHR) binds numerous molecules present in the environment and is a therapeutic target for MS: however, its precise function in T lymphocytes, the orchestrators of MS, has not been described. Here, we show that CD4 specific Ahr knockout drives recovery in EAE by a decreasing T cell fitness. At the mechanistic level, we show that the absence of AHR changes the gut microenvironment composition to generate metabolites, such as bile salts and short chain fatty acids, that impact T cell viability and influence disease recovery. Our study demonstrates a newly emerging role for AHR in mediating the interdependence between T lymphocytes and the microbiota while identifying new potential molecular targets for the treatment of MS and other autoimmune diseases.One Sentence SummaryThe aryl hydrocarbon receptor modulates the gut microenvironment to promote autoimmunity in a mouse model of multiple sclerosis.

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