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 h omeostasis, prevention of autoimmune disorders, and the goal of transplanta tion. Recent studies suggest that certain cytokines, notably IL-10 and TGF- beta, may play a role in downregulating immune functions. To further examin e the role of cytokines in Ag-specific hyporesponsiveness, murine CD4(+) T cells were exposed ex vivo to alloantigen-bearing stimulators in the presen ce of exogenous IL-10 and/or TGF-beta. Primary but not secondary alloantige n proliferative responses were inhibited by IL-10 alone. However, the combi ned addition of TL-10+ TGF-beta markedly induced alloantigen hyporesponsive ness in both primary and secondary MLR cultures. Alloantigen-specific hypor esponsiveness was observed also under conditions in which nominal Ag respon ses were intact, In adoptive transfer experiments, IL-10 + TGF-beta-treated CD4(+) T cells, but not T cells treated with either cytokine alone, mere m arkedly impaired in inducing graft-vs-host disease alloresponses to MHC cla ss II disparate recipients. These data provide the first formal evidence th at IL-10 and TGF-beta have at least an additive effect in inducing alloanti gen-specific tolerance, and that in vitro cytokines can be exploited to sup press CD4(+) T cell-mediated Ag-specific responses in vivo.