McGargill M A, Hogquist K A
Department of Lab Medicine and Pathology and the Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
J Immunol. 1999 Feb 1;162(3):1237-45.
The various stages of T cell development are typically characterized by the expression level of the two coreceptors, CD4 and CD8. During the CD4+CD8+ (double-positive, DP) stage of development, thymocytes that perceive a low avidity signal through the TCR go on to differentiate (positive selection), and ultimately down-regulate one coreceptor to express either CD4 or CD8. Alternatively, thymocytes that perceive a high avidity signal down-regulate both coreceptors and are induced to die via apoptosis (negative selection). However, it has recently been suggested that positively selected thymocytes may also partially down-regulate both coreceptors before up-regulating the one coreceptor that is ultimately expressed. This would imply that coreceptor down-regulation (dulling) is not a consequence of commitment to the death pathway. To explore this possibility, we have utilized an in vitro assay to demonstrate that dulling occurred in response to both positive and negative selecting ligands in vitro, was not a result of nonspecific membrane perturbation, was not dependent on the type of APC, and occurred before death in vitro. Furthermore, when thymocyte apoptosis was blocked, CD4 and CD8 were down-regulated in response to TCR stimulation. These data suggest that dulling in response to TCR ligation is distinct from death, and support a model in which DP dulling occurs during both positive and negative selection. The biological implications of this phenomenon are discussed.
T细胞发育的各个阶段通常以两种共受体CD4和CD8的表达水平为特征。在发育的CD4+CD8+（双阳性，DP）阶段，通过TCR感知到低亲和力信号的胸腺细胞会继续分化（阳性选择），最终下调一种共受体以表达CD4或CD8。或者，感知到高亲和力信号的胸腺细胞会下调两种共受体，并通过凋亡被诱导死亡（阴性选择）。然而，最近有人提出，经过阳性选择的胸腺细胞在上调最终表达的一种共受体之前，也可能会部分下调两种共受体。这意味着共受体下调（钝化）不是走向死亡途径的结果。为了探究这种可能性，我们利用体外试验证明，钝化在体外对阳性和阴性选择配体均有反应，不是非特异性膜扰动的结果，不依赖于抗原呈递细胞的类型，且在体外死亡之前就已发生。此外，当胸腺细胞凋亡被阻断时，CD4和CD8会因TCR刺激而下调。这些数据表明，对TCR连接的钝化与死亡不同，并支持一种模型，即DP钝化在阳性和阴性选择过程中均会发生。本文讨论了这一现象的生物学意义。
