Canté-Barrett Kirsten, Gallo Elena M, Winslow Monte M, Crabtree Gerald R
Department of Developmental Biology, Howard Hughes Medical Institute, Stanford University, CA 94305, USA.
J Immunol. 2006 Feb 15;176(4):2299-306. doi: 10.4049/jimmunol.176.4.2299.
The processes of positive and negative selection in the thymus both determine the population of T cells that will enter the peripheral immune system and eliminate self-reactive T cells by apoptosis. Substantial evidence indicates that TCR signal intensity mediates this cell fate choice: low-intensity signals lead to survival and differentiation, whereas high-intensity signals generated by self-Ag lead to cell death. The molecular mechanism by which these graded signals are converted to discrete outcomes is not understood. Positive selection requires the Ca(2+)-dependent phosphatase calcineurin, whereas negative selection requires the proapoptotic Bcl-2 family member Bcl-2-interacting mediator of cell death (Bim). In this study, we investigated the regulation of Bim expression and the role of Ca(2+) in mediating negative selection. Our results show that transcription is necessary for both negative selection and Bim induction. Surprisingly, we also found that Ca(2+) is necessary for Bim induction. Induction of bim transcription appears to involve protein kinase C, but not calcineurin, JNK, p38 MAPK, or MEK. These results localize the decision point in positive vs negative selection to a step downstream of Ca(2+) signaling and suggest that negative selection signals induce Ca(2+)-dependent bim transcription through PKC.
胸腺中的阳性和阴性选择过程都决定了进入外周免疫系统的T细胞群体，并通过凋亡消除自身反应性T细胞。大量证据表明，TCR信号强度介导了这种细胞命运选择：低强度信号导致存活和分化，而自身抗原产生的高强度信号导致细胞死亡。这些分级信号如何转化为离散结果的分子机制尚不清楚。阳性选择需要Ca(2+)依赖性磷酸酶钙调神经磷酸酶，而阴性选择需要促凋亡Bcl-2家族成员细胞死亡的Bcl-2相互作用介质（Bim）。在本研究中，我们研究了Bim表达的调控以及Ca(2+)在介导阴性选择中的作用。我们的结果表明，转录对于阴性选择和Bim诱导都是必需的。令人惊讶的是，我们还发现Ca(2+)对于Bim诱导是必需的。bim转录的诱导似乎涉及蛋白激酶C，但不涉及钙调神经磷酸酶、JNK、p38 MAPK或MEK。这些结果将阳性与阴性选择的决策点定位到Ca(2+)信号传导的下游步骤，并表明阴性选择信号通过PKC诱导Ca(2+)依赖性bim转录。
