However, these studies relied on transient pharmacological inhibition shortly after activation, and therefore the role of BET bromodomains during T cell subset differentiation and their potential therapeutic application remain to be defined. A recent report has revealed a variety of alterations in T cell cytokine production as a consequence of BET bromodomain inhibition ( Bandukwala et al., 2012). Indeed, BET proteins work as chromatin regulators that recruit transcriptional co-activators, such as P-TEFb, to promote gene transcription in inflammation ( Hargreaves et al., 2009 Nicodeme et al., 2010) and cancer ( Filippakopoulos et al., 2010 Dawson et al., 2011 Mertz et al., 2011 Zuber at al., 2011). BET polypeptides BRD2, BRD3, BRD4, and BRDT harbor tandem bromodomain motifs that bind acetylated lysine residues in histones, thereby linking changes in chromatin structure with gene transcription. Although these and other studies have begun to shed light on the role of chromatin dynamics in the control of immune lineage specification and function ( Araki et al., 2009 Ramirez-Carrozzi et al., 2009), how these changes are integrated is still poorly understood. Global analysis of histone modifications in T cells has revealed remarkable differences in the chromatin structure of distinct T helper subsets and some of their signature transcription factors ( Wei et al., 2009). To differentiate into T H17 cells, naive T cells require the combined exposure to TGF-β1 and IL-6, and it is now well established that these two factors work in concert to drive the induction of a transcriptional signature that is largely orchestrated by a group of transcriptional regulators that includes steroid receptor-type nuclear receptors RORγt and RORα ( Ivanov et al., 2006 Yang et al., 2008), IRF4 (IFN regulatory factor 4 Brüstle et al., 2007 Ciofani et al., 2012 Glasmacher et al., 2012), AP-1 transcription factor Batf ( Schraml et al., 2009), the proto-oncogene c-Maf ( Bauquet et al., 2009), NF-κB family member c-Rel ( Chen et al., 2011 Ruan et al., 2011), and AHR (aryl hydrocarbon receptor Veldhoen et al., 2008). It is now widely recognized that T H17 cells, a subset of T helper cells which produce IL-17A, IL-17F, IL-21, IL-22, and GM-CSF, mediate autoimmune conditions including multiple sclerosis, psoriasis, rheumatoid arthritis, and Crohn’s disease, as well as the murine models of these diseases ( Bettelli et al., 2006 Korn et al., 2009 Littman and Rudensky, 2010). The dysregulated activation and expansion of CD4 + T cells lie at the core of autoimmune disorders. 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. 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.
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 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. 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. It is also firmly established that their aberrant generation and activation results in autoimmune conditions. Interleukin (IL) 17–producing T helper (T H17) cells have been selected through evolution for their ability to control fungal and bacterial infections.
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