Iwata M, Hanaoka S, Sato K
Laboratories of Cellular Immunology, Mitsubishi Kasei Institute of Life Sciences, Tokyo, Japan.
Eur J Immunol. 1991 Mar;21(3):643-8. doi: 10.1002/eji.1830210316.
Positive and negative selection events are involved in determining useful T cell clones to mature in the thymus. Accumulating evidence suggests that immature self-reactive thymocytes undergo apoptotic death (negative selection) upon stimulation via the T cell receptors (TcR). A similar phenomenon of activation-induced death has been reported in T cell hybridomas. On the other hand, little is known about the mechanism of the positive selection. Apoptosis in rodent thymocytes or T cell hybridomas is also known to be induced by glucocorticoids in vitro at concentrations within the physiologic range. We report here that the TcR/CD3-mediated stimulation and glucocorticoids mutually inhibit the apoptosis in T cell hybridomas. The production of interleukin 2 by the rescued cells indicated that the TcR/CD3-mediated signal was transduced into the cells. Thymocytes were also rescued from glucocorticoid-induced apoptosis by the stimulation with antibodies to TcR/CD3 molecules. The rescue of thymocytes, however, was observed only at a narrow concentration range of each of the antibodies, suggesting that the proper stimulation via the TcR/CD3 is required for the rescue. If thymocytes in situ are differentially stimulated according to the affinity of the TcR towards self, only the thymocytes whose TcR have proper affinity towards self may be rescued from glucocorticoid-induced apoptosis. Therefore, we propose a hypothesis that the positive selection of the T cell repertoire is based on the inhibition of glucocorticoid-induced apoptosis in immature thymocytes bearing TcR with proper affinity for self by the TcR-mediated signals in situ. Furthermore, the selection may be influenced by the peak level of glucocorticoid concentration, since the proper concentration range of the anti-TcR/CD3 antibody for the rescue was variable depending on the glucocorticoid concentration.
阳性和阴性选择事件参与决定在胸腺中成熟的有用T细胞克隆。越来越多的证据表明，未成熟的自身反应性胸腺细胞在通过T细胞受体（TcR）受到刺激后会经历凋亡死亡（阴性选择）。在T细胞杂交瘤中也报道了类似的激活诱导死亡现象。另一方面，关于阳性选择的机制知之甚少。已知在体外，生理范围内浓度的糖皮质激素可诱导啮齿动物胸腺细胞或T细胞杂交瘤发生凋亡。我们在此报告，TcR/CD3介导的刺激和糖皮质激素相互抑制T细胞杂交瘤中的凋亡。获救细胞产生白细胞介素2表明TcR/CD3介导的信号被转导到细胞中。用针对TcR/CD3分子的抗体刺激也可使胸腺细胞从糖皮质激素诱导的凋亡中获救。然而，仅在每种抗体的狭窄浓度范围内观察到胸腺细胞的获救，这表明通过TcR/CD3进行适当刺激是获救所必需的。如果原位胸腺细胞根据TcR对自身的亲和力受到不同刺激，那么只有那些TcR对自身具有适当亲和力的胸腺细胞可能会从糖皮质激素诱导的凋亡中获救。因此，我们提出一个假说，即T细胞库的阳性选择是基于原位TcR介导的信号对具有对自身适当亲和力的TcR的未成熟胸腺细胞中糖皮质激素诱导凋亡的抑制。此外，这种选择可能受糖皮质激素浓度峰值水平的影响，因为用于获救的抗TcR/CD3抗体的适当浓度范围会因糖皮质激素浓度而异。
