Deletion of a Class IIb Histone/protein Deacetylase (HDAC), HDAC10, Enhances FoxP3+ T-regulatory (Treg) Cell Suppressive Function, Gene Expression and Metabolism, and Promotes Allograft Survival

Abstract

Abstract Treg cells control immune responses that cause unwarranted inflammation and promote allograft rejection, leading to interest in their therapeutic applications. Targeting HDACs to modulate the function of Tregs has practical advantages over injecting ex-vivo-expanded Tregs that may not survive long post-injection. Several of the 11 classical HDAC enzymes are necessary for optimal Treg function while others are dispensable. We evaluated the function of HDAC10 in murine Tregs. We showed that HDAC10 bound to Foxp3 in co-immunoprecipitation assays, and that germ-line knockout of this hitherto enigmatic HDAC had no effect on the health of targeted mice. We found that HDAC10 deletion: (i) enhanced Treg suppressive function both in vitro (Treg suppression assays) and in vivo (homeostatic proliferation assays), compared to wild-type (WT) Tregs; (ii) increased Treg expression of genes including Foxp3, Granzyme-B, IL-10 and others (microarray, qPCR); (iii) increased acetylation of NFkB/p65 at lysine 310 and thereby prolonged the nuclear retention of p65 and increased transcription from p65-dependent promoters; and (iv) increased oxidative phosphorylation in Tregs compared to WT Tregs (assays of mitochondrial function on the Seahorse platform). Lastly, heterotopic cardiac allograft studies (BALB/c->C57BL/6) showed that compared to WT recipients, HDAC10−/− allograft recipients had markedly prolonged allograft survival (p<0.01). While additional studies of the in vivo effects of HDAC10 deletion in transplant and autoimmune models, including colitis, are underway our data show promise for the therapeutic targeting of HDAC10 as a novel approach for transplant rejection and other immunologically mediated disorders.