IL-10 induces a long-lasting antigen-specific anergic state in human CD4⁺ T cells. Human CD4⁺ T cells activated by allogeneic monocytes in a primary mixed lymphocyte reaction in the presence of exogenous IL-10 fail to proliferate after restimulation with the same alloantigens. A comparable state of T cell unresponsiveness can be induced by activation of CD4⁺ T cells by cross-linked anti-CD3 monoclonal antibodies (mAbs) in the presence of exogenous IL-10. Anergized T cells fail to produce IL-2, IL-5, IL-10, interferon γ, tumor necrosis factor α, and granulocyte/macrophage colony-stimulating factor. The IL-10-induced anergic state is long-lasting. T cell anergy cannot be reversed after restimulation with anti-CD3 and anti-CD28 mAbs, although CD3 and CD28 expression is normal. Restimulation of anergized T cells with anti-CD3 mAbs induces normal Ca²⁺ fluxes and results in increased CD3, CD28, and class II MHC expression, indicating that calcineurin-mediated signaling occurs in these anergic cells. However, the expression of the IL-2 receptor α chain is not upregulated, which may account for the failure of exogenous IL-2 to reverse the anergic state. Interestingly, anergic T cells and their nonanergic counterparts show comparable levels of proliferation and cytokine production after activation with phorbol myristate acetate and Ca²⁺ ionophore, indicating that a direct activation of a protein kinase C-dependent pathway can overcome the tolerizing effect of IL-10. These data demonstrate that IL-10 induces T cell anergy and may play an important role in the induction and maintenance of antigen-specific T cell tolerance. IL-10 has been shown to inhibit antigen-specific activation and proliferation of human peripheral blood T cells and T cell clones belonging to the Th0, Th1, or Th2 subsets. These inhibitory effects were indirect and mediated through inhibition of the function of APCs. IL-10 regulates constitutive and IFN-γ- or IL-4-induced class II MHC expression on monocytes, dendritic cells and Langerhans cells. In addition, IL-10 inhibits the expression of CD54 (intercellular adhesion molecule-1, the ligand for LFA-1), CD80, and CD86 (ligands for CD28) which function as important costimulatory molecules for T cell activation. Recently, it has been shown that IL-10 also has a direct effect on CD4⁺ T by suppressing IL-2 secretion. Similar to its inhibitory effects on T cell proliferation in response to soluble antigens, IL-10 stronglyIL-10 induces a long-lasting antigen-specific anergic state in human CD4⁺ T cells. Human CD4⁺ T cells activated by allogeneic monocytes in a primary mixed lymphocyte reaction in the presence of exogenous IL-10 fail to proliferate after restimulation with the same alloantigens. A comparable state of T cell unresponsiveness can be induced by activation of CD4⁺ T cells by cross-linked anti-CD3 monoclonal antibodies (mAbs) in the presence of exogenous IL-10. Anergized T cells fail to produce IL-2, IL-5, IL-10, interferon γ, tumor necrosis factor α, and granulocyte/macrophage colony-stimulating factor. The IL-10-induced anergic state is long-lasting. T cell anergy cannot be reversed after restimulation with anti-CD3 and anti-CD28 mAbs, although CD3 and CD28 expression is normal. Restimulation of anergized T cells with anti-CD3 mAbs induces normal Ca²⁺ fluxes and results in increased CD3, CD28, and class II MHC expression, indicating that calcineurin-mediated signaling occurs in these anergic cells. However, the expression of the IL-2 receptor α chain is not upregulated, which may account for the failure of exogenous IL-2 to reverse the anergic state. Interestingly, anergic T cells and their nonanergic counterparts show comparable levels of proliferation and cytokine production after activation with phorbol myristate acetate and Ca²⁺ ionophore, indicating that a direct activation of a protein kinase C-dependent pathway can overcome the tolerizing effect of IL-10. These data demonstrate that IL-10 induces T cell anergy and may play an important role in the induction and maintenance of antigen-specific T cell tolerance. IL-10 has been shown to inhibit antigen-specific activation and proliferation of human peripheral blood T cells and T cell clones belonging to the Th0, Th1, or Th2 subsets. These inhibitory effects were indirect and mediated through inhibition of the function of APCs. IL-10 regulates constitutive and IFN-γ- or IL-4-induced class II MHC expression on monocytes, dendritic cells and Langerhans cells. In addition, IL-10 inhibits the expression of CD54 (intercellular adhesion molecule-1, the ligand for LFA-1), CD80, and CD86 (ligands for CD28) which function as important costimulatory molecules for T cell activation. Recently, it has been shown that IL-10 also has a direct effect on CD4⁺ T by suppressing IL-2 secretion. Similar to its inhibitory effects on T cell proliferation in response to soluble antigens, IL-10 strongly