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RORα enforces stability of the T-helper-17 cell effector program

Lee, J.-Y.; Hall, J. A.; Pokrovskii, M.; Kroehling, L.; Wu, L.; Littman, D. R.

2020-12-22 immunology
10.1101/2020.12.15.422921 bioRxiv
Show abstract

T helper 17 (Th17) cells regulate mucosal barrier defenses, but also promote multiple autoinflammatory diseases. Although many molecular determinants of Th17 cell differentiation have been described, the transcriptional programs that sustain Th17 cells in vivo remain obscure. The transcription factor ROR{gamma}t is critical for Th17 cell differentiation, but a distinct role of the closely-related ROR, which is co-expressed in Th17 cells, is not known. Here we demonstrate that, although dispensable for Th17 cell differentiation, ROR governs optimal Th17 responses in peripheral tissues. Thus, the absence of ROR in T cells led to significant reductions in both ROR{gamma}t expression and effector function amongst Th17 cells, due to need for cooperative ROR and ROR{gamma}t binding to a newly-identified Rorc enhancer element that is essential for Th17 lineage maintenance in vivo. Altogether, these data point to a non-redundant role of ROR in Th17 lineage maintenance via reinforcement of the ROR{gamma}t transcriptional program.

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