Erlacher Miriam, Knoflach Michael, Stec Ilona E M, Böck Günther, Wick Georg, Wiegers G Jan
Division of Experimental Pathophysiology and Immunology, Biocenter, Innsbruck Medical University, Austria.
Eur J Immunol. 2005 Nov;35(11):3287-96. doi: 10.1002/eji.200526279.
Signaling by either the TCR or glucocorticoid receptor (GR) induces apoptosis in thymocytes. Interestingly, it has been shown previously that hybridoma T cells escape apoptosis induced by either TCR or GR when both of these receptors signal simultaneously. Whether such mutual antagonism is present in primary thymocytes was the subject of the present study. Both glucocorticoids (GC) and anti-TCR/CD28 (or anti-CD3/CD28) mAb induced apoptosis in total thymocytes. When these signals were present at the same time, GC-induced apoptosis was partially inhibited by TCR/CD3 signaling. Costimulation by anti-CD28 enhanced the inhibitory effects of anti-CD3 on GC-induced apoptosis about 30-fold. However, subset analysis revealed that most cells rescued from GC-induced apoptosis were mature CD4+ and CD8+ thymocytes, and these cells were resistant to TCR/CD3-induced apoptosis in the absence of GC. Similar results were obtained with mature splenic CD4+ and CD8+ T cells. TCR/CD3 signaling alone, while inducing apoptosis in CD4+(CD8+)TCRlow thymocytes, rescued a small subset of CD4+(CD8+)TCRlow thymocytes from GC-induced apoptosis. Thus, TCR signaling increasingly reverses GC-induced apoptosis as thymocyte development progresses. As GC are infinitely present in vivo, these findings support a model wherein TCR signaling may be required to prevent GC-induced apoptosis both under basal and immune challenging conditions.
T细胞受体（TCR）或糖皮质激素受体（GR）发出的信号可诱导胸腺细胞凋亡。有趣的是，先前已有研究表明，当这两种受体同时发出信号时，杂交瘤T细胞可逃避由TCR或GR诱导的凋亡。原发性胸腺细胞中是否存在这种相互拮抗作用是本研究的主题。糖皮质激素（GC）和抗TCR/CD28（或抗CD3/CD28）单克隆抗体均可诱导总胸腺细胞凋亡。当这些信号同时存在时，TCR/CD3信号传导可部分抑制GC诱导的凋亡。抗CD28的共刺激将抗CD3对GC诱导凋亡的抑制作用增强了约30倍。然而，亚群分析显示，从GC诱导的凋亡中挽救出来的大多数细胞是成熟的CD4+和CD8+胸腺细胞，并且这些细胞在没有GC的情况下对TCR/CD3诱导的凋亡具有抗性。成熟的脾脏CD4+和CD8+ T细胞也获得了类似的结果。单独的TCR/CD3信号传导在诱导CD4+（CD8+）TCRlow胸腺细胞凋亡的同时，挽救了一小部分CD4+（CD8+）TCRlow胸腺细胞免于GC诱导的凋亡。因此，随着胸腺细胞发育的进展，TCR信号传导越来越多地逆转GC诱导的凋亡。由于GC在体内大量存在，这些发现支持了一种模型，即在基础和免疫挑战条件下，可能都需要TCR信号传导来预防GC诱导的凋亡。
