Zhang J, Somani A K, Watt S, Mills G B, Siminovitch K A
Department of Immunology, University of Toronto, The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Ontario, Canada.
J Immunol. 1999 Jun 1;162(11):6359-67.
Restimulation of Ag receptors on peripheral T lymphocytes induces tyrosine phosphorylation-based signaling cascades that evoke Fas ligand expression and induction of Fas-mediated programmed cell death. In view of the role for the Src homology domain 2-bearing protein tyrosine phosphatase-1 (SHP-1) in modulating TCR signaling, we investigated the influence of SHP-1 on TCR-mediated apoptosis by assaying the sensitivity of peripheral T cells from SHP-1-deficient viable motheaten (mev) mice to cell death following TCR restimulation. The results of these studies revealed mev peripheral T cells to be markedly more sensitive than wild-type cells to induction of cell death following TCR stimulation. By contrast, PMA/ionophore and anti-Fas Ab-induced apoptotic responses were no different in mev compared with wild-type activated cells. Enhanced apoptosis of TCR-restimulated mev lymphocytes was associated with marked increases in Fas ligand expression as compared with wild-type cells, but was almost abrogated in both mev and wild-type cells by Fas-Fc treatment. Thus, the increased sensitivity of mev T cells to apoptosis following TCR restimulation appears to reflect a TCR-driven phenomenon mediated through up-regulation of Fas-Fas ligand interaction and induction of the Fas signaling cascade. These findings, together with the hyperproliferative responses of mev peripheral T cells to initial TCR stimulation, indicate that SHP-1 modulation of TCR signaling translates to the inhibition of both T cell proliferation and activation and, as such, is likely to play a pivotal role in regulating the expansion of Ag-stimulated T cells during an immune response.
外周T淋巴细胞上Ag受体的再刺激会诱导基于酪氨酸磷酸化的信号级联反应，引发Fas配体表达并诱导Fas介导的程序性细胞死亡。鉴于含Src同源结构域2的蛋白酪氨酸磷酸酶-1（SHP-1）在调节TCR信号传导中的作用，我们通过检测来自SHP-1缺陷的可行的动性震颤（mev）小鼠的外周T细胞在TCR再刺激后对细胞死亡的敏感性，研究了SHP-1对TCR介导的细胞凋亡的影响。这些研究结果显示，mev外周T细胞在TCR刺激后对细胞死亡诱导的敏感性明显高于野生型细胞。相比之下，PMA/离子载体和抗Fas Ab诱导的凋亡反应在mev细胞与野生型活化细胞之间没有差异。与野生型细胞相比，TCR再刺激的mev淋巴细胞凋亡增强与Fas配体表达的显著增加有关，但在mev和野生型细胞中，Fas-Fc处理几乎都消除了这种凋亡增强。因此，mev T细胞在TCR再刺激后对细胞凋亡敏感性增加似乎反映了一种由TCR驱动的现象，该现象通过Fas-Fas配体相互作用的上调和Fas信号级联反应的诱导介导。这些发现，连同mev外周T细胞对初始TCR刺激的过度增殖反应，表明SHP-1对TCR信号传导的调节转化为对T细胞增殖和活化的抑制，因此，在免疫反应期间调节Ag刺激的T细胞扩增中可能起关键作用。
