The study by Groux et al. demonstrates that human CD4+ T cells, when activated by allogeneic monocytes in the presence of interleukin-10 (IL-10), fail to proliferate and produce cytokines such as IL-2, IL-5, IL-10, interferon γ, tumor necrosis factor α, and granulocyte/macrophage colony-stimulating factor. This anergic state is long-lasting and cannot be reversed by exogenous IL-2 or anti-CD28 stimulation. The anergic T cells still express normal levels of CD3 and CD28, indicating that the TCR/CD3 complex is not downregulated. However, they fail to upregulate the IL-2 receptor α chain (CD25), which may account for the inability to respond to exogenous IL-2. Interestingly, these anergic T cells can be reactivated by stimulation with phorbol myristate acetate and Ca2+ ionophore, suggesting that a direct activation of protein kinase C-dependent pathways can overcome the tolerizing effect of IL-10. The findings suggest that IL-10 plays a crucial role in the induction and maintenance of antigen-specific T cell tolerance, potentially contributing to transplantation tolerance and GVHD prevention.The study by Groux et al. demonstrates that human CD4+ T cells, when activated by allogeneic monocytes in the presence of interleukin-10 (IL-10), fail to proliferate and produce cytokines such as IL-2, IL-5, IL-10, interferon γ, tumor necrosis factor α, and granulocyte/macrophage colony-stimulating factor. This anergic state is long-lasting and cannot be reversed by exogenous IL-2 or anti-CD28 stimulation. The anergic T cells still express normal levels of CD3 and CD28, indicating that the TCR/CD3 complex is not downregulated. However, they fail to upregulate the IL-2 receptor α chain (CD25), which may account for the inability to respond to exogenous IL-2. Interestingly, these anergic T cells can be reactivated by stimulation with phorbol myristate acetate and Ca2+ ionophore, suggesting that a direct activation of protein kinase C-dependent pathways can overcome the tolerizing effect of IL-10. The findings suggest that IL-10 plays a crucial role in the induction and maintenance of antigen-specific T cell tolerance, potentially contributing to transplantation tolerance and GVHD prevention.