Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198.
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198.
J Immunol. 2018 Jan 15;200(2):483-499. doi: 10.4049/jimmunol.1601793. Epub 2017 Dec 6.
T cells use the endocytic pathway for key cell biological functions, including receptor turnover and maintenance of the immunological synapse. Some of the established players include the Rab GTPases, the SNARE complex proteins, and others, which function together with EPS-15 homology domain-containing (EHD) proteins in non-T cell systems. To date, the role of the EHD protein family in T cell function remains unexplored. We generated conditional EHD1/3/4 knockout mice using CD4-Cre and crossed these with mice bearing a myelin oligodendrocyte glycoprotein-specific TCR transgene. We found that CD4 T cells from these mice exhibited reduced Ag-driven proliferation and IL-2 secretion in vitro. In vivo, these mice exhibited reduced severity of experimental autoimmune encephalomyelitis. Further analyses showed that recycling of the TCR-CD3 complex was impaired, leading to increased lysosomal targeting and reduced surface levels on CD4 T cells of EHD1/3/4 knockout mice. Our studies reveal a novel role of the EHD family of endocytic recycling regulatory proteins in TCR-mediated T cell functions.
T 细胞利用内吞途径来完成关键的细胞生物学功能，包括受体更新和免疫突触的维持。其中一些已确定的参与者包括 Rab GTPases、SNARE 复合物蛋白等，它们与非 T 细胞系统中的 EPS-15 同源结构域（EHD）蛋白一起发挥作用。迄今为止，EHD 蛋白家族在 T 细胞功能中的作用仍未得到探索。我们使用 CD4-Cre 生成了条件性 EHD1/3/4 敲除小鼠，并将这些小鼠与携带髓鞘少突胶质细胞糖蛋白特异性 TCR 转基因的小鼠进行了杂交。我们发现，这些小鼠的 CD4 T 细胞表现出体外 Ag 驱动的增殖和 IL-2 分泌减少。在体内，这些小鼠表现出实验性自身免疫性脑脊髓炎严重程度降低。进一步的分析表明，TCR-CD3 复合物的再循环受到损害，导致 EHD1/3/4 敲除小鼠的溶酶体靶向增加和表面水平降低。我们的研究揭示了 EHD 家族内吞再循环调节蛋白在 TCR 介导的 T 细胞功能中的新作用。
