HDAC10 Targeting Regulates Foxp3 Promoter, Enhances T-regulatory (Treg) Function and Suppresses Autoimmune Colitis

Abstract

Abstract Targeting histone/protein deacetylases (HDACs), especially by isoform-selective targeting, has major promise as a means to enhance the function of Tregs and thereby suppress immune-related disorders, such as colitis. We present data on the functions of HDAC10 in Treg cells. We found that HDAC10 binds to the Foxp3 promoter in the Tregs, is able to physically bind and deacetylate Foxp3 (at K31), and regulates the transcriptional activity of the Foxp3 promoter. Next, we evaluated the function of HDAC10 using HDAC10 KO mice. Overall, such mice were healthy and 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) modestly enhanced the stability of monomeric Foxp3 (reducing gels) but the oligomeric forms, which are more relevant functionally, were increased by more than two-fold (native gels); (iii) increased H3K4Me3 (activating) marks on Foxp3 promoter and the key regulatory region of Foxp3 promoter-CNS2; and (iv) enhanced binding of ATF/CREB and FoxO1 at the Foxp3 promoter and CNS2 sites. We then evaluated the effects of HDAC10 deletion in Tregs in colitis models using adoptively transferred Rag1 KO mice. We found that HDAC10 KO Tregs were superior to WT Tregs in: (i) a ‘prevention of induction’ model of colitis, whereby WT T effector cells were injected with a limiting ratio of Tregs that allowed for weight loss as an indicator of colitis; and (ii) rescuing from colitis. Studies to develop and test HDAC10-specific inhibitors are currently underway. Overall, we show that HDAC10 has a key role in Foxp3+ Treg cells, and is an important new target for therapeutic intervention in autoimmune diseases, including colitis.