Induction of CD4(+) T cell alloantigen-specific hyporesponsiveness by IL-10 and TGF-beta(1)

Induction and maintenance of Ag-specific tolerance are pivotal for immune homeostasis, prevention of autoimmune disorders, and the goal of transplantation. Recent studies suggest that certain cytokines, notably IL-10 and TGF-beta, may play a role in downregulating immune functions. To further examine the role of cytokines in Ag-specific hyporesponsiveness, murine CD4(+) T cells were exposed ex vivo to alloantigen-bearing stimulators in the presence of exogenous IL-10 and/or TGF-beta. Primary but not secondary alloantigen proliferative responses were inhibited by IL-10 alone. However, the combined addition of TL-10+ TGF-beta markedly induced alloantigen hyporesponsiveness in both primary and secondary MLR cultures. Alloantigen-specific hyporesponsiveness was observed also under conditions in which nominal Ag responses were intact, In adoptive transfer experiments, IL-10 + TGF-beta-treated CD4(+) T cells, but not T cells treated with either cytokine alone, mere markedly impaired in inducing graft-vs-host disease alloresponses to MHC class II disparate recipients. These data provide the first formal evidence that IL-10 and TGF-beta have at least an additive effect in inducing alloantigen-specific tolerance, and that in vitro cytokines can be exploited to suppress CD4(+) T cell-mediated Ag-specific responses in vivo.