Foxp3+ T-regulatory (Treg) cells are key regulators of immune responses that can result in unwarranted inflammation and promote allograft rejection. From a theoretical perspective, targeting histone/protein deacetylases (HDACs), of which there are eleven, to modulate the function of Tregs has considerable practical advantages in allograft recipients compared to injecting at some point post-transplant a bolus of variably pure Treg cells that may or may not survive very long after injection. However, consistent with a one size does not fit all concept, certain HDACs have proven absolutely required for optimal Treg function whereas others appear to be dispensable. Our task has been to determine which is which. The current studies assessed the role of a hitherto enigmatic HDAC, HDAC10, in murine Treg cells. We demonstrated that HDAC10 bound to Foxp3 in co-immunoprecipitation assays, and that germ-line knockout of this hitherto enigmatic HDAC had no effect on the overall health of targeted mice. Importantly, we found that HDAC10 deletion: (i) boosted Treg suppressive function in vitro compared to wild-type (WT) Tregs, (ii) increased Treg expression of Foxp3, Ctla4, Granzyme-b, Il-10 and other genes (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 (OCR and ECAR 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 markedly prolonged allograft survival (p<0.01). Studies to further dissect the in vivo impact of HDAC10 deletion in additional experimental transplant and autoimmune models are underway, as are efforts directed at developing selective targeting of HDAC10 using pharmacologic inhibitors. Overall, these data show the promise for therapeutic targeting of HDAC10 as a novel approach for transplant rejection and potentially other immunologically mediated disorders.

CITATION INFORMATION: Dahiya S, Wang L, Beier U, Angelin A, Han R, Wallace D, Hancock W. Mechanistic Insights into How Targeting of HDAC10 Promotes Foxp3+ Treg Cell Suppressive Activity, Gene Expression and Metabolism, and Enhances Allograft Survival. Am J Transplant. 2016;16 (suppl 3).

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