BET bromodomain inhibition suppresses T _H17-mediated pathology

Abstract

The BET family of chromatin adaptors promotes T _H17 differentiation, and inhibition of BET proteins protects against autoimmune diseases, including collagen-induced arthritis and EAE, in mice.

Abstract

Interleukin (IL) 17–producing T helper (T _H17) cells have been selected through evolution for their ability to control fungal and bacterial infections. It is also firmly established that their aberrant generation and activation results in autoimmune conditions. Using a characterized potent and selective small molecule inhibitor, we show that the bromodomain and extra-terminal domain (BET) family of chromatin adaptors plays fundamental and selective roles in human and murine T _H17 differentiation from naive CD4 ⁺ T cells, as well as in the activation of previously differentiated T _H17 cells. We provide evidence that BET controls T _H17 differentiation in a bromodomain-dependent manner through a mechanism that includes the direct regulation of multiple effector T _H17-associated cytokines, including IL17, IL21, and GMCSF. We also demonstrate that BET family members Brd2 and Brd4 associate with the Il17 locus in T _H17 cells, and that this association requires bromodomains. We recapitulate the critical role of BET bromodomains in T _H17 differentiation in vivo and show that therapeutic dosing of the BET inhibitor is efficacious in mouse models of autoimmunity. Our results identify the BET family of proteins as a fundamental link between chromatin signaling and T _H17 biology, and support the notion of BET inhibition as a point of therapeutic intervention in autoimmune conditions.