IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells

CD4(+) T regulatory type 1 (Tr1) cells suppress Ag-specific immune response s in vitro and in vivo. Although IL-10 is critical for the differentiation of Tr1 cells, the effects of other cytokines on differentiation of naive T cells into Tr1 cells have not been investigated. Here we demonstrate that e ndogenous or exogenous IL-10 in combination with IFN-alpha, but not TGF-bet a, induces naive CD4(+) T cells derived from cord blood to differentiate in to Tt1 cells: IL-10(+)IFN-gamma +IL-2(-/low)IL-4(-). Naive CD4(+) T cells d erived from peripheral blood require both exogenous IL-10 and IFN-alpha for Tr1 cell differentiation. The proliferative responses of the Tr1-containin g lymphocyte populations, following activation with anti-CD3 and anti-CD28 mAbs, were reduced. Similarly, cultures containing Tr1 cells displayed redu ced responses to alloantigens via a mechanism that was partially mediated b y IL-10 and TGF-beta. More importantly, Tr1-containing populations strongly suppressed responses of naive T cells to alloantigens. Collectively, these results show that IFN-alpha strongly enhances IL-10-induced differentiatio n of functional Tri cells, which represents a first major step in establish ing specific culture conditions to generate T regulatory cells for biologic al and biochemical analysis, and for cellular therapy to induce peripheral tolerance in humans.