(454g) Cytokine-like Regulation of T-Cell Fate Mediated By Tryptophan-Derived Microbiota Metabolites

Investigating the functional role of the microbiota in human health and its regulation of the immune system is one of the most exciting and impactful areas of biomedical research. However, despite the undeniable link between the microbiota and human health, the mechanisms used by the microbiota to mediate beneficial and deleterious effects on host immunity are poorly understood. An emerging mechanistic paradigm is that communication of the microbiota with host immunity is mediated via distinct non-host derived metabolites, such as short chain fatty acids. Prior work from our labs demonstrated that tryptophan- (Trp)-derived metabolites are an abundant and novel class of immunomodulatory microbiota signals that regulate inflammation as well as are novel endogenous ligands of the aryl hydrocarbon receptor (AhR) (Sridharan et al., 2014; Jin et al., 2014). With the growing number of pivotal roles that the AhR has for host immunity, particularly in the gastrointestinal (GI) tract, we hypothesized that microbiota-derived Trp-metabolites are important mediators of GI tract mucosal immunity, in particular, CD4+ and CD8+ T-cell function. We screened a panel of six Trp metabolites for their ability to regulate T-cell differentiation. Of these, two metabolites - indole and 5-hydroxyindole (5-HI) - exhibited the strongest and most interesting properties. We determined that indole promoted the differentiation of naïve T-cells to Tregs, both in the absence and presence of Treg skew cytokines. At the same time, indole also attenuated the differentiation of naïve T-cells to Th17 cells under Th17 skew conditions. In contrast, 5-HI inhibited Tregs while promoting Th17 and Th1 development and function. In co-conditioning experiments, the T-cell instructing activities of indole were dominant over 5-HI. Since both indole and 5-HI are bona fide ligands for the AhR, we used AhR^-/- mice to determine that indole’s effects on T-cell differentiation are AhR-dependent, while 5-HI’s effects are largely AhR-independent. A similar reciprocal regulation by indole and 5-HI was observed with human T-cells. Our work shows that two microbiota-produced small molecules, indole and 5-hydroxyindole, have reciprocal and contrasting roles for regulating T-lymphocyte fate and function and indicate novel “cytokine-like properties” for these metabolites.

Funding: This is supported by the NIH 1R01 AI110642-01