Negative regulation of T H 17-mediated inflammation by the nuclear receptor REV-ERBβ

SUMMARY T H 17 cells play a central role in several human autoimmune diseases. We and others reported the nuclear receptor, REV-ERBα, as a cell-intrinsic repressor of T H 17-mediated pathogenicity. REV-ERBβ, REV-ERBα’s closely related family member, is thought to be functionally redundant to REV-ERBα, which we sought to explore in T H 17-mediated immunity. Our data indicate that deletion of REV-ERBβ enhances T H 17-mediated pro-inflammatory cytokine expression and exacerbated disease in mouse models of multiple sclerosis and colitis. RNA-sequencing indicates REV-ERBβ and REV-ERBα do not have similar transcriptional profiles. REV-ERBβ does not appear to regulate gene expression through interaction with the classic co-repressor NCoR1, which is in contrast to REV-ERBα in T H 17 cells, nor does it utilize heme, its known endogenous ligand for its repressive functions. Our results establish that while REV-ERBβ also acts as a negative regulator of T H 17-cell function and pathogenicity, it does so in a manner that is non-redundant, independent, and unique to REV-ERBα.