Kemper Claudia, Chan Andrew C, Green Jonathan M, Brett Kelly A, Murphy Kenneth M, Atkinson John P
Division of Rheumatology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Nature. 2003 Jan 23;421(6921):388-92. doi: 10.1038/nature01315.
The immune system must distinguish not only between self and non-self, but also between innocuous and pathological foreign antigens to prevent unnecessary or self-destructive immune responses. Unresponsiveness to harmless antigens is established through central and peripheral processes. Whereas clonal deletion and anergy are mechanisms of peripheral tolerance, active suppression by T-regulatory 1 (Tr1) cells has emerged as an essential factor in the control of autoreactive cells. Tr1 cells are CD4+ T lymphocytes that are defined by their production of interleukin 10 (IL-10) and suppression of T-helper cells; however, the physiological conditions underlying Tr1 differentiation are unknown. Here we show that co-engagement of CD3 and the complement regulator CD46 in the presence of IL-2 induces a Tr1-specific cytokine phenotype in human CD4+ T cells. These CD3/CD46-stimulated IL-10-producing CD4+ cells proliferate strongly, suppress activation of bystander T cells and acquire a memory phenotype. Our findings identify an endogenous receptor-mediated event that drives Tr1 differentiation and suggest that the complement system has a previously unappreciated role in T-cell-mediated immunity and tolerance.
免疫系统不仅必须区分自身与非自身，还必须区分无害的和病理性的外来抗原，以防止不必要的或自我毁灭性的免疫反应。对无害抗原的无反应性是通过中枢和外周过程建立的。虽然克隆清除和失能是外周耐受的机制，但T调节性1（Tr1）细胞的主动抑制已成为控制自身反应性细胞的一个重要因素。Tr1细胞是CD4 + T淋巴细胞，其特征在于产生白细胞介素10（IL-10）并抑制辅助性T细胞；然而，Tr1分化的生理条件尚不清楚。在这里，我们表明，在IL-2存在的情况下，CD3与补体调节因子CD46的共同结合在人CD4 + T细胞中诱导出Tr1特异性细胞因子表型。这些受CD3/CD46刺激产生IL-10的CD4 +细胞强烈增殖，抑制旁观者T细胞的活化，并获得记忆表型。我们的研究结果确定了一个驱动Tr1分化的内源性受体介导事件，并表明补体系统在T细胞介导的免疫和耐受中具有先前未被认识的作用。
