Xiao Yun, Qiao Guilin, Tang Juan, Tang Rong, Guo Hui, Warwar Samantha, Langdon Wallace Y, Tao Lijian, Zhang Jian
Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China; Department of Nephrology, The First Affiliated Hospital, Guangzhou Medical University, 510120 Guangzhou, People's Republic of China;
Section of Nephrology, Department of Medicine, The University of Chicago, Chicago, IL 60637; and.
J Immunol. 2015 Nov 1;195(9):4218-27. doi: 10.4049/jimmunol.1501200. Epub 2015 Sep 28.
Previously, we demonstrated that CD28 and CTLA-4 signaling control Casitas-B-lineage lymphoma (Cbl)-b protein expression, which is critical for T cell activation and tolerance induction. However, the molecular mechanism(s) of this regulation remains to be elucidated. In this study, we found that Cbl-b fails to undergo tyrosine phosphorylation upon CD3 stimulation because SHP-1 is recruited to and dephosphorylates Cbl-b, whereas CD28 costimulation abrogates this interaction. In support of this finding, T cells lacking SHP-1 display heightened tyrosine phosphorylation and ubiquitination of Cbl-b upon TCR stimulation, which correlates with decreased levels of Cbl-b protein. The aberrant Th2 phenotype observed in T cell-specific Shp1(-/-) mice is reminiscent of heightened Th2 response in Cblb(-/-) mice. Indeed, overexpressing Cbl-b in T cell-specific Shp1(-/-) T cells not only inhibits heightened Th2 differentiation in vitro, but also Th2 responses and allergic airway inflammation in vivo. Therefore, SHP-1 regulates Cbl-b-mediated T cell responses by controlling its tyrosine phosphorylation and ubiquitination.
此前，我们证明CD28和CTLA-4信号通路控制着Casitas-B系淋巴瘤（Cbl）-b蛋白的表达，这对T细胞活化和耐受诱导至关重要。然而，这种调控的分子机制仍有待阐明。在本研究中，我们发现Cbl-b在CD3刺激后无法发生酪氨酸磷酸化，因为SHP-1被招募至Cbl-b并使其去磷酸化，而CD28共刺激可消除这种相互作用。支持这一发现的是，缺乏SHP-1的T细胞在TCR刺激后显示出Cbl-b酪氨酸磷酸化和泛素化增强，这与Cbl-b蛋白水平降低相关。在T细胞特异性Shp1(-/-)小鼠中观察到的异常Th2表型让人联想到Cblb(-/-)小鼠中增强的Th2反应。事实上，在T细胞特异性Shp1(-/-) T细胞中过表达Cbl-b不仅在体外抑制增强的Th2分化，而且在体内抑制Th2反应和过敏性气道炎症。因此，SHP-1通过控制Cbl-b的酪氨酸磷酸化和泛素化来调节Cbl-b介导的T细胞反应。
