IL-10 induces regulatory T cell apoptosis by up-regulation of the membrane form of TNF-α

Numerous studies have demonstrated the role of regulatory T (Treg) cells in peripheral tolerance. Nevertheless, how the survival and death of Treg cells is controlled is largely unknown. In this study, we investigated the mechanisms involved in regulating the homeostasis of a subset of Ag-specific alphabetaTCR(+) CD4(-)CD8(-) double negative (DN) Treg cells. We demonstrate that DN Treg cells are naturally resistant to TCR cross-linking-induced apoptosis. Administration of exogenous IL-10 renders DN Treg cells susceptible to apoptosis, and abolishes their suppressive function. Furthermore, TCR cross-linking of DN Treg cells in the presence of IL-10 leads to the up-regulation of the membrane-bound but not the soluble form of TNF-alpha. Interaction of membrane bound TNF-a with TNFR2 sends death signals to DN Treg cells. Blocking their interaction can reverse the effects. of IL-10 on DN Treg cells. These results provide insights into the mechanisms that regulate the function and homeostasis of DN Treg cells.