Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function

• Published in: Scientific reports 2017-08, Vol.7 (1), p.8626-11, Article 8626
• Main Authors: Huang, Jianbing, Wang, Liqing, Dahiya, Satinder, Beier, Ulf H., Han, Rongxiang, Samanta, Arabinda, Bergman, Joel, Sotomayor, Eduardo M., Seto, Edward, Kozikowski, Alan P., Hancock, Wayne W.
• Format: Article
• Language: English
• Subjects: 38/39; 38/77; 42/41; 45/15; 45/61; 631/250/2520; 64/60; 692/308/1426; 82/80; 96/31; Allografts; Animal models; Arteriosclerosis; Autoimmune diseases; Clonal deletion; Foxp3 protein; Heart diseases; Heart transplantation; Histone deacetylase; Humanities and Social Sciences; Inhibitors; Lymphocytes T; Major histocompatibility complex; multidisciplinary; Science; Science (multidisciplinary); Survival; Transplantation; Transplants & implants
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-09211-3

Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-β. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II-mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases.