Persistence of FOXP3 expression is impaired in RR-MS Tregs (99.3)

Abstract

Abstract Impaired Treg function may contribute to the development of Multiple Sclerosis (MS). FOXP3 is required for Treg function and its expression is maintained by the common γ-chain cytokines through phosphorylation of STAT5 (pSTAT5). We examined the pSTAT5 levels of CD4+CD25+Treg from relapsing remitting MS and control subjects in response to low-dose IL-2. We found that, despite equivalent levels of CD25, pSTAT5 was lower in RR-MS subjects (p= 0.0013), indicating a mechanism by which FOXP3 expression and Treg function may be lost in MS. To further examine the expression and persistence of FOXP3 in these subjects we generated adaptive Tregs and followed FOXP3 expression in these cells over time. We found that the initial induction of FOXP3 was similar to that of controls, but by day 10 of culture FOXP3 expression in CD4+CD25+ T cells was significantly lower (p<0.0001). FOXP3 expression could not be rescued by IL-2, IL-7 or IL-2/IL-7 in combination. In addition, cell surface expression of CD122 and CD132 is significantly decreased on RR-MS CD4+ CD25+ T cells. Taken together we conclude that the impaired persistence of FOXP3 expression in aTreg may impact the number and function of Tregs in individuals with RR-MS. This loss of FOXP3 may be due to decreased pSTAT5 in response to IL-2 and IL-7 which may be due to decreased levels of the IL-2R and IL-7R complexes. This work was supported by grants from the JDRF33-2008-398 and DFG108312-1.