HDACs in Immunity
HDAC7 in Thymocyte Development
Class IIA HDACs are a widely expressed, conserved family of transcriptional regulators with crucial roles in development and disease. Their activity is controlled via phosphorylation of N-terminal serine residues that dictate nuclear vs. cytoplasmic localization, which in turn determines what target transcription factors (e.g., MEF2) are bound by an N-terminal adapter domain. At most sites, class IIA HDACs repress target loci either by direct binding – converting activators into repressors – or as part of a large NCoR/SMRT-HDAC3 corepressor complex.
HDAC7 is a class IIA member highly expressed in developing thymocytes, and we have uncovered crucial roles for this protein in controlling multiple aspects of T-cell development. In conventional T-cells, loss of HDAC7 strongly inhibits positive selection by shortening thymocyte lifespan and altering tonic MAPK activity. In contrast, a gain of function HDAC7 mutant (HDAC7-ΔP, where N-terminal serines are mutated to prevent nuclear export) results in a robust block in negative selection and the escape of autoreactive T-cells out into the periphery.
Building on this previous work in conventional (naïve) T-cells, the Verdin lab is now focused on understanding the role of HDAC7 in the development of so-called agonist-selected T-cells. This class of T-cells, including tTregs, invariant natural killer T-cells (iNKTs), CD8 intraepitheilial cells (IELs), and MR1-associated invariant T-cells (MAIT), are thought to receive stronger than-normal TCR signals during thymic residence yet manage to escape negative selection and leave the thymus as non-naïve effectors. We believe we have uncovered a crucial role for HDAC7 in regulating the development of these agonist-selected T-cells by licensing the acquisition of the innate effector pathway that gives them many mature effector properties (non-circulating tissue residence, robust cytokine production ability and limited proliferative potential).
Interestingly, the gain-of-function HDAC7-ΔP mutant develops striking tissue-specific autoimmunity characterized by obliterative exocrine pancreatitis and extensive lymphocytic infiltrates in stomach, liver, and intestine. We hypothesize that the combination of blocked negative selection in conventional T-cells and disruption in the development of homeostatic innate effectors contributes to this constellation of tissue-specific autoimmunity. HDAC7 has been implicated in GWAS studies as containing susceptibility loci for both primary sclerosing cholangitis (PSC) and inflammatory bowel disease, and we believe that our work holds important therapeutic implications in ameliorating and treating these autoimmune conditions.
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