Oxysterols are expressed in T lymphocytes and impair type 1 regulatory CD4 T-cell differentiation

Abstract

Oxysterols, oxidised forms of cholesterol, have recently been assigned with novel functions in modulating the immune response. More specifically, the enzyme cholesterol 25 hydroxylase (ch25h), the rate-limiting step to synthetize 25-hydroxycholesterol (25-OHC) from cholesterol, has been proposed to control viral infection and Immunoglobulin secretion. However the function of oxysterols in CD4+ T lymphocytes and their role during autoimmune diseases has not been assessed. The development and progression of multiple sclerosis results in part from the balance between pathogenicity of effector CD4+ T cells and negative regulation imposed by regulatory cells. Since the original classification of CD4+ T lymphocytes into TH1 and TH2 subsets, the repertoire of effector CD4+ T cell subsets has expanded to include additional effector T cell subsets like TH17 cells and regulatory T cell subsets, in particular Foxp3+ regulatory T-cells (Tregs) and IL-10-producing T regulatory type 1 (TR1). Regulatory IL-10-producing-type 1 (Tr1) T cells are instrumental in the prevention of autoimmune diseases and multiple sclerosis and IL-27 is a critical factor for Tr1 cell differentiation. We assessed the expression of Ch25h and 25-OHC in subset of CD4+ T cells differentiated in vitro. We found that Ch25h expression was specifically induced by IL-27 in Tr1 cells. We further demonstrated that 25-OHC prevented TR1 cell development both in vitro and in vivo and dissected the underlying signaling pathways. Together, our findings show that Ch25h and 25-OHC act as negative regulators of TR1 cell both in vitro and in vivo. Not only these findings unravel novel molecular mechanisms accounting for the generation of Tr1 cells, but they also provide oxysterols as critical players to regulate differentiation of Tr1 cells and to inhibit development of autoimmunity.