Leitenberg D, Boutin Y, Constant S, Bottomly K
Howard Hughes Medical Institute, Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
J Immunol. 1998 Aug 1;161(3):1194-203.
To define the role of CD4 in modulating T cell signaling pathways and regulating Th1 and Th2 differentiation, we have examined the activation and differentiation characteristics of naive T cells from CD4 mutant mice. Using peptides with differing affinities for the moth cytochrome c-specific TCR, we test the hypothesis that differences in coreceptor recruitment and signaling explain the qualitatively distinct signaling pathways seen in CD4 T cells following high affinity agonist and low affinity altered peptide ligand (APL) ligation. We find that the absence of CD4 signaling during stimulation with a strong agonist peptide does not qualitatively change the pattern of early TCR-mediated biochemical signaling events into a pattern resembling the response of CD4+ T cells to APLs. In contrast, the response to APL stimulation, by T cells bearing the same TCR, does require a component of CD4 signaling. The proliferative response and calcium signals normally seen following APL stimulation are markedly diminished in the absence of CD4. In addition, we find that naive T cell differentiation into Th2 effector cells is impaired in the absence of CD4. These data suggest that the altered pattern of biochemical signals generated by APLs require CD4 coreceptor function and that some of these signals may be required to initiate Th2 differentiation.
为了确定CD4在调节T细胞信号通路以及调控Th1和Th2分化中的作用，我们研究了来自CD4突变小鼠的初始T细胞的激活和分化特征。使用对蛾细胞色素c特异性TCR具有不同亲和力的肽段，我们检验了以下假设：共受体募集和信号传导的差异解释了在高亲和力激动剂和低亲和力改变肽配体（APL）连接后CD4 T细胞中所见的定性不同的信号通路。我们发现，在用强激动剂肽刺激期间缺乏CD4信号传导并不会将早期TCR介导的生化信号事件模式定性地改变为类似于CD4 + T细胞对APL的反应模式。相反，具有相同TCR的T细胞对APL刺激的反应确实需要CD4信号传导的一个组成部分。在没有CD4的情况下，APL刺激后通常所见的增殖反应和钙信号明显减弱。此外，我们发现，在没有CD4的情况下，初始T细胞向Th2效应细胞的分化受损。这些数据表明，APL产生的生化信号改变模式需要CD4共受体功能，并且这些信号中的一些可能是启动Th2分化所必需的。
