Groux H, Bigler M, de Vries J E, Roncarolo M G
Human Immunology Department, DNAX Research Institute of Molecular and Cellular Biology, Inc., Palo Alto, California 94304-1104, USA.
J Exp Med. 1996 Jul 1;184(1):19-29. doi: 10.1084/jem.184.1.19.
Human CD4+ T cells, activated by allogeneic monocytes in a primary mixed lymphocyte reaction in the presence of exogenous interleukin (IL) 10, specifically failed to proliferate after restimulation with the same alloantigens. A comparable state of T cell unresponsiveness could be induced by activation of CD4+ T cells by cross-linked anti-CD3 monoclonal antibodies (mAbs) in the presence of exogenous IL-10. The anergic T cells failed to produce IL-2, IL-5, IL-10, interferon gamma, tumor necrosis factor alpha, and granulocyte/macrophage colony-stimulating factor. The IL-10-induced anergic state was long-lasting. T cell anergy could not be reversed after restimulation of the cells with anti-CD3 and anti-CD28 mAbs, although CD3 and CD28 expression was normal. In addition, restimulation of anergized T cells with anti-CD3 mAbs induced normal Ca2+ fluxes and resulted in increased CD3, CD28, and class II major histocompatibility complex expression, indicating that calcineurin-mediated signaling occurs in these anergic cells. However, the expression of the IL-2 receptor alpha chain was 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 showed 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. Taken together, these data demonstrate that IL-10 induces T cell anergy and therefore may play an important role in the induction and maintenance of antigen-specific T cell tolerance.
在存在外源性白细胞介素（IL）-10的情况下，人CD4⁺T细胞在初次混合淋巴细胞反应中被同种异体单核细胞激活后，再次用相同的同种抗原刺激时特别未能增殖。在存在外源性IL-10的情况下，通过交联抗CD3单克隆抗体（mAb）激活CD4⁺T细胞可诱导出类似的T细胞无反应状态。无反应性T细胞未能产生IL-2、IL-5、IL-10、γ干扰素、肿瘤坏死因子α和粒细胞/巨噬细胞集落刺激因子。IL-10诱导的无反应状态是持久的。在用抗CD3和抗CD28 mAb再次刺激细胞后，T细胞无反应性无法逆转，尽管CD3和CD28表达正常。此外，用抗CD3 mAb再次刺激无反应性T细胞可诱导正常的Ca²⁺通量，并导致CD3、CD28和II类主要组织相容性复合体表达增加，表明钙调神经磷酸酶介导的信号传导在这些无反应性细胞中发生。然而，IL-2受体α链的表达未上调，这可能解释了外源性IL-2无法逆转无反应状态的原因。有趣的是，无反应性T细胞及其非无反应性对应物在用佛波酯肉豆蔻酸酯和Ca²⁺离子载体激活后显示出相当水平的增殖和细胞因子产生，表明蛋白激酶C依赖性途径的直接激活可以克服IL-10的耐受作用。综上所述，这些数据表明IL-10诱导T细胞无反应性，因此可能在抗原特异性T细胞耐受的诱导和维持中起重要作用。
