While the Foxp3 promoter and its three associated conserved non-coding sequence (CNS)/enhancer regions have received much attention, literally nothing is known of the contribution of the evolutionarily highly conserved co-repressor complexes, CoREST, NCoR/SMRT, NuRD and Sin3, to T-regulatory (Treg) cell biology. These multi-protein nuclear complexes are typically recruited by, and repress, transcription factors. We studied the CoREST complex, whose members include CoREST, Hdac1, Hdac2 and Lsd1 (Kdm1a), in transduced cells and in murine Foxp3+ Tregs, at the molecular, protein, cellular and in vivo levels, by conditional targeting using Foxp3cre and floxed genes, and newly developed pharmacologic inhibitors. Conditional deletion of CoREST (Rcor1), or its pharmacologic inhibition, impaired Treg function, as did Hdac1 deletion in Tregs, whereas conditional deletion of Hdac2, or use of Hdac2 selective inhibitors enhanced Treg function. Biochemical and co-immunoprecipitation studies showed that Hdac2 deletion increased the association of CoRest with Hdac1. Conditional Hdac1 deletion had no effect on the corresponding association of CoRest with Hdac2, and promoted IL-2, IFN-g and IL-17 production within the Treg population under basal conditions, and even more so when cells were exposed to pro-inflammatory cytokines such as IL-6. Corresponding in vivo studies showed that deletion of Hdac1 in Tregs impaired Treg-dependent fully MHC-disparate cardiac allograft survival and prevented costimulation blockade-induced cardiac allograft tolerance induction, as did use of the CoREST inhibitor (all p<0.01). In contrast, conditional deletion or pharmacologic targeting of Hdac2 promoted cardiac allograft survival (p<0.01). Hence, these data show that (i) Hdac1, Lsd1 and CoREST together serve to regulate normal Foxp3+ Treg cell gene expression and suppressive functions in vitro and in vivo, and (ii) the vital functions of the CoREST transcription repressor complex in Tregs can be further enhanced by Hdac2 targeting. These studies bring new insights into the dynamic composition and functions of multimolecular complexes in Foxp3+ Treg cells.

CITATION INFORMATION: Wang L, Samanta A, Levine M, Beier U, Han R, Kalin J, Holson E, Cole P, Hancock W. Vital Role of the CoREST Complex as a Master Regulator of Foxp3+ T-Regulatory Cell Gene Expression and Suppressive Function. Am J Transplant. 2017;17 (suppl 3).

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