The microbiota-derived signal indole regulates T-cell fate by reciprocal control of Th17 and Treg development
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The presence of a normal microbiota and immune regulation in the gut limits the onset of several inflammatory disorders. However, the specific microbiota mechanisms or chemical effectors that promote homeostasis are largely unknown. Previously, we reported that indole, a microbiota-derived (not host derived) tryptophan-metabolite, attenuates indicators of inflammation in intestinal epithelial cells. In addition, we show that indole treatment rescues mice from colitis in vivo. Based on our results, we hypothesized that indole influences mucosal CD4 T-cell function. Because Foxp3+ regulatory T cells (Tregs) and pro-inflammatory Th17 cells are key players in the balance of gut homeostasis, we tested the impact of indole on Treg and Th17 development. Here, we reveal that indole regulates Treg/Th17 lineage fate by dramatically augmenting TGF-β-induced Treg expansion, function, and stability. Interestingly, indole also promoted Treg Foxp3 expression independent of TGF-β or IL-2 suggesting a novel mechanism for the induction of Foxp3 expression in CD4 T cells. In a reciprocal fashion, indole inhibited Th17 development via STAT3 and RORgt pathways and decreased IL-17 production. These data reveal a novel mechanistic paradigm on how the microbiota influence mucosal immunobiology and establish the metabolite indole as a potent regulator of Treg and Th17 cell balance. Moreover, our results suggest microbiota-derived metabolites offer a rich pool of potent immunomodulatory compounds.
author list (cited authors)
Katepalli, M., Mueller, C., Steinmeyer, S., Jayaraman, A., & Alaniz, R.
complete list of authors
Katepalli, Madhu||Mueller, Carrie||Steinmeyer, Shelby||Jayaraman, Arul||Alaniz, Robert