IL-10 induces a long term antigen-specific anergic state in human CD4+ T cells

The observation that interleukin-10 (IL-10) inhibits proliferation and cytokine production by alloreactive T cells prompted us to investigate whether IL-10 plays a role in the induction of T-cell anergy. Indeed, stimulation of human peripheral blood C/J4⁺ T cells with either allogeneic monocytes or cross-linked anti-CD3 mAb, in the presence of IL-10, results in a complete unresponsiveness of these cells, in the absence of any cell death. Restimulation of these unresponsive T cells with alloantigens or anti-CD3 mAb failed to induce IL-2, IL-4, IL-10, GM-CSF, IFN-γ and TNF-α production. In addition, the T cells did not express the IL-2Rα chain (CD25) and did not proliferate. The T-cell unresponsiveness could not be reversed by restimulating the cells via the TcR/CD3 complex in the presence of exogenous IL-2 or anti-CD28 mAb, but the cells proliferated in response to TPA and Ca⁺⁺ ionophore. The clonal analysis of these anergic CD4⁺ T cells after stimulation with high doses of CD3 mAb (500 //g/ml), reveals a subset of CD4⁺ T helper cells with a new cytokine profile : no IL-2 and IL-4 production but very high levels of IL-10 and normal levels of IL-5, TNF-α and IFN-7. This cytokine profile is reminiscent of that observed in anergic host reactive T-cell clones isolated from human SCID patients engrafted with HLA mismatched stem cells. In these patients, high levels of endogenous IL-10 production are associated with tolerance in vivo. These findings support the notion that IL-10 may play an important role in inducing tolerance after allogeneic transplantation.