摘要：SummaryA skewed tryptophan metabolism has been reported in patients with lupus. Here, we investigated the mechanisms by which it occurs in lupus-susceptible mice, and how tryptophan metabolites exacerbate T cell activation. Metabolomic analyses demonstrated that tryptophan is differentially catabolized in lupus mice compared to controls and that the microbiota played a role in this skewing. There was no evidence for differential expression of tryptophan catabolic enzymes in lupus mice, further supporting a major contribution of the microbiota to skewing. However, isolated lupus T cells processed tryptophan differently, suggesting a contribution of T cell intrinsic factors. Functionally, tryptophan and its microbial product tryptamine increased T cell metabolism and mTOR activation, while kynurenine promoted interferon gamma production, all of which have been associated with lupus. These results showed that a combination of microbial and T cell intrinsic factors promotes the production of tryptophan metabolites that enhance inflammatory phenotypes in lupus T cells.Graphical abstractDisplay OmittedHighlights•Intestinal dysbiosis skews tryptophan catabolism in lupus-prone mice•Murine lupus CD4+T cells have an intrinsically different processing of tryptophan•Tryptophan and tryptamine increase mTOR activation and metabolism in CD4+T cells•Kynurenine promotes IFNγ production in CD4+T cells from lupus-prone miceBiological sciences; Human metabolism; Immunology; Cell biology
