Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation
Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation
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DOI：
10.1073/pnas.97.15.8439
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发表时间：
2000-07-18
影响因子：
11.1
通讯作者：
Morimoto, C
中科院分区：
文献类型：
--
作者：
Ikushima, H;Munakata, Y;Morimoto, C
CD 26是已知结合腺苷脱氨酶并具有二肽基肽酶IV活性的T细胞活化抗原。CD 26和CD 3与固定化mAb的交联可以递送有助于T细胞活化的共刺激信号。我们早期的研究表明，CD 26的交联诱导其内化。参与信号通路的许多蛋白质的磷酸化。以及随后的T细胞增殖。虽然这些发现表明内化在CD 26功能中的重要性，但CD 26在其胞质区域中仅具有6个氨基酸残基，没有已知的内吞作用基序。在本研究中，我们已经确定了甘露糖6-磷酸/胰岛素样生长因子II受体（M6 P/IGFIIR）作为CD 26的结合蛋白，并且CD 26的碳水化合物部分中的甘露糖6-磷酸（M6 P）残基对于这种结合至关重要。外周血T细胞的活化导致CD 26的甘露糖6磷酸化。此外，CD 26与抗CD 26抗体的交联不仅诱导CD 26的加帽和内化，而且诱导CD 26与M6 P/IGFIIR的共定位。最后，CD 26的内化和由CD 26介导的共刺激诱导的T细胞增殖反应都被M6 P抑制，但不被葡萄糖6-磷酸或甘露糖1-磷酸。这些结果表明交联后CD 26的内化部分由MGP/IGFIIR介导，并且甘露糖6-磷酸化的CD 26和M6 P/IGFIIR之间的相互作用可能在CD 26介导的T细胞共刺激信号传导中起重要作用。
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 l-phosphate. These results indicate that internalization of CD26 after crosslinking is mediated in part by MGP/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.