Thymocyte apoptosis induced by T cell activation is, mediated by glucocorticoids in vivo
Thymocyte apoptosis induced by T cell activation is, mediated by glucocorticoids in vivo
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DOI：
10.4049/jimmunol.169.4.1837
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发表时间：
2002-08-15
影响因子：
4.4
通讯作者：
Muglia, LJ
中科院分区：
文献类型：
--
作者：
Brewer, JA;Kanagawa, O;Muglia, LJ
糖皮质激素以药理剂量给药，有效地调节免疫系统功能，是许多常见人类疾病的主要治疗方法。糖皮质激素的生理产生可能在中枢和外周免疫系统的优化中发挥作用。可能的影响包括淋巴细胞发育的改变和细胞因子反应的下调，但基本作用尚不清楚。为了确定内源性糖皮质激素在胸腺细胞发育中的作用，我们使用缺乏糖皮质激素受体GRKO的小鼠胎肝对致死照射的野生型(WT)小鼠进行免疫重建。我们发现了GRko胸腺细胞的正态数量和亚群分布。GRKO胸腺细胞在体外对抗CD3epsilon抗体诱导的细胞凋亡也表现出与WT胸腺细胞相似的敏感性。令人惊讶的是，在体内，GRKO胸腺细胞比WT胸腺细胞对抗CD3 epsilon介导的胸腺细胞凋亡的抵抗力明显更强。与这一发现一致的是，在体内，TCR复合体的激活诱导了持续高水平的糖皮质激素，这与WT小鼠的胸腺细胞凋亡密切相关。我们发现，虽然TCR复合体的直接结合可能导致一部分胸腺细胞死亡，但大多数胸腺细胞的缺失需要糖皮质激素。因此，在体内，用单抗刺激TCR可能比阴性选择更准确地反映多克隆T细胞的激活情况。
Glucocorticoids, administered in pharmacological doses, potently modulate immune system function and are a mainstay therapy for many common human diseases. Physiologic production of glucocorticoids may play a role in optimization of the immune repertoire both centrally and peripherally. Possible effects include alteration of lymphocyte development and down-regulation of cytokine responses, but essential roles remain unclear. To determine the part that endogenous glucocorticoids play in thymocyte development, we used fetal liver from mice lacking the glucocorticoid receptor GRko for immunological reconstitution of lethally irradiated wild-type (WT) mice. We find normal numbers and subset distribution of GRko thymocytes. GRko thymocytes also exhibit similar sensitivity to apoptosis induced by activating anti-CD3epsilon Ab as WT thymocytes in vitro. Surprisingly, GRko thymocytes are significantly more resistant than WT thymocytes to anti-CD3epsilon-mediated thymocyte apoptosis in vivo. Consistent with this finding, in vivo TCR complex activation induces sustained high levels of glucocorticoids that correlate strongly with thymocyte apoptosis in WT mice. We find that while direct engagement of the TCR complex may cause death of a subset of thymocytes, glucocorticoids are required for deletion of the majority of thymocytes. Thus, TCR stimulation by Ab administration may more accurately reflect polyclonal T cell activation than negative selection in vivo.