Wayne Hancock, MBBS, PhD, professor of pathology and laboratory medicine at the University of Pennsylvania in Philadelphia, described the highly conserved corepressor complex (CoREST) as a master regulator of Foxp3+ Treg cells. The CoREST complex includes histone deacetylase 1 (HDAC1) and HDAC2 and, using both in vitro and in vivo studies, the investigators identified contrasting effects of HDAC1 and HDAC2 deletion on regulatory T cell function. Specifically, HDAC1 deletion disrupts the CoREST complex, decreases induced Treg (iTreg) development, and impairs Treg function. Deletion of HDAC1 thus resulted in decreased Treg expression of CoREST. In contrast, deletion of HDAC2 increases CoREST function and enhances Treg function. So, despite their high structural homology and dimerization within the CoREST complex of regulatory T cells, HDAC1 and HDAC2 hold opposite roles.

Using this information, the investigators sought to develop CoREST inhibitors. They identified some that had dose-dependent effects and could be used as tools to pharmacologically target Tregs. In addition, they developed kinetically selective HDAC2i compounds that were able to promote regulatory T cell function. Their work thus brings new insights into the dynamic composition and functions of multimolecular complexes in Foxp3+ Treg cells and reveals some pharmacological options for influencing these cells.

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