CD4+CD25+ T regs with acetylated FoxP3 are associated with immune suppression in human leprosy

•We investigated T regs mediated immune suppression in leprosy.•TGF-β dependent demethylation of FoxP3 promoter.•TGF-β leads to induction of FoxP3 in CD4+CD45RA+/RO+CD25− T cells.•FoxP3 acetylation determines T reg cell's suppressive potential.

Leprosy is a chronic human disease that results from infection of Mycobacterium leprae. T reg cells have been shown to have important implications in various diseases. However, in leprosy, it is still unclear whether T regs can mediate immune suppression during progression of the disease. In the present study, we have proposed the putative mechanism leading to high proportion of T reg cells and investigated its significance in human leprosy. High levels of TGF-β followed by adaptation of FoxP3+ naive and memory (CD4+CD45RA+/RO+) T cells were observed as the principal underlying factors leading to higher generation of T reg cells during disease progression. Furthermore, TGF-β was found to be associated with increased phosphorylation-mediated-nuclear-import of SMAD3 and NFAT towards BL/LL pole to facilitate FoxP3 expression in these cells, the same as justified after using nuclear inhibitors of SMAD3 (SIS3) and NFAT (cyclosporin A) in CD4+CD25+ cells in the presence of TGF-β and IL-2. Interestingly, low ubiquitination of FoxP3 in T reg cells of BL/LL patients was revealed to be a major driving force in conferring stability to FoxP3 which in turn is linked to suppressive potential of T regs. The present study has also pinpointed the presence of CD4+CD25+IL-10+ sub class of T regs (Tr1) in leprosy.