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Structure and function of memory T cell marker CD26

记忆T细胞标志物CD26的结构和功能

基本信息

批准号：
11694248
负责人：
MORIMOTO Chikao
金额：
$ 2.56万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11694248/
关键词：
CD26 M6P IGFIIR T cell costimulation Dipeptidyl peptidase IV ADA binding protein interrnalization CD4メモリーT細胞 ADA T細胞共刺激インスリン成長因子II受容体

项目摘要

CD26 is a T cell activation antigen known to bind adenosine deaminase and have dipeptidyl peptidase IV activity. Cross-linking of CD26 and CD3 with immobilized mAbs can deliver a costimulatory signal that contributes to T cell activation. Our earlier studies revealed that cross-linking of CD26 induces its internalization, the phosphorylation of a number of proteins involved in the signaling pathway, and subsequent T cell proliferation. Although these findings suggest the importance of internalization in the function of CD26, CD26 has only 6 aa residues in its cytoplasmic region with no known motif for endocytosis. In the present study, we have identified the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGFIIR) as a binding protein for CD26 and that mannose 6-phosphate (M6P) residues in the carbohydrate moiety of CD26 are critical for this binding. Activation of peripheral blood T cells results in the mannose 6 phosphorylation of CD26. In addition, the cross-linking of CD26 with an anti-CD26 antibody induces not only capping and internalization of CD26 but also colocalization of CD26 with M6P/IGFIIR.Finally, both internalization of CD26 and the T cell proliferative response induced by CD26-mediated costimulation were inhibited by the addition of M6P, but not by glucose 6-phosphate or mannose 1-phosphate. These results indicate that internalization of CD26 after cross-linking is mediated in part by M6P/IGFIIR and that the interaction between mannose 6-phosphorylated CD26 and M6P/IGFIIR may play an important role in CD26-mediated T cell costimulatory signaling.

CD26是一种已知与腺苷脱氨酶结合的T细胞活化抗原，具有二肽基肽酶IV活性。CD26和CD3与固定化单抗的交联可以传递有助于T细胞活化的共刺激信号。我们早期的研究表明，CD26的交联会诱导其内化，使信号通路中的一些蛋白磷酸化，从而导致T细胞的增殖。尽管这些发现提示了内化在CD26功能中的重要性，但CD26的细胞质区域只有6个氨基酸残基，没有已知的内吞基序。在本研究中，我们已经确定6-磷酸甘露糖/胰岛素样生长因子II受体(M6P/IGFIIR)是CD26的结合蛋白，并且CD26糖链上的甘露糖6-磷酸(M6P)残基是这种结合的关键。外周血T细胞的激活导致CD26的甘露糖6磷酸化。此外，CD26与抗CD26抗体的交联不仅可诱导CD26的内化，还可导致CD26与M6P/IGFIIR的共定位。最后，加入M6P可抑制CD26的内化和CD26介导的共刺激诱导的T细胞增殖反应，但不能被6-磷酸葡萄糖或1-磷酸甘露糖所抑制。这些结果表明，CD26的内化部分是由M6P/IGFIIR介导的，甘露糖6-磷酸化的CD26与M6P/IGFIIR之间的相互作用可能在CD26介导的T细胞共刺激信号中起重要作用。