Jenkins M K, Schwartz R H, Pardoll D M
Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.
Science. 1988 Sep 23;241(4873):1655-8. doi: 10.1126/science.241.4873.1655.
Cyclosporine A (CsA) is an important immunosuppressive drug that is widely used in transplantation medicine. Many of its suppressive effects on T cells appear to be related to the inhibition of T cell receptor (TCR)-mediated activation events. Paradoxically, in certain situations CsA is responsible for the induction of a T cell-mediated autoimmunity. The effects of CsA on T cell development in the thymus were investigated to elucidate the physiologic events underlying this phenomenon. Two major effects were revealed: (i) CsA inhibits the development of mature single positive (CD4+8- or CD4-8+) TCR-alpha beta+ thymocytes without discernibly affecting CD4-8- TCR-gamma delta+ thymocytes and (ii) CsA interferes with the deletion of cells bearing self-reactive TCRs in the population of single positive thymocytes that do develop. This suggests a direct mechanism for CsA-induced autoimmunity and may have implications for the relative contribution of TCR-mediated signaling events in the development of the various T cell lineages.
环孢素A（CsA）是一种重要的免疫抑制药物，广泛应用于移植医学。它对T细胞的许多抑制作用似乎与抑制T细胞受体（TCR）介导的激活事件有关。矛盾的是，在某些情况下，CsA会导致T细胞介导的自身免疫。为了阐明这一现象背后的生理事件，研究了CsA对胸腺中T细胞发育的影响。结果揭示了两个主要影响：（i）CsA抑制成熟单阳性（CD4+8-或CD4-8+）TCR-αβ+胸腺细胞的发育，而对CD4-8-TCR-γδ+胸腺细胞没有明显影响；（ii）CsA干扰了在确实发育的单阳性胸腺细胞群体中携带自身反应性TCR的细胞的清除。这提示了CsA诱导自身免疫的直接机制，并且可能对TCR介导的信号事件在各种T细胞谱系发育中的相对贡献具有启示意义。
