Structure and function of memory T cell marker CD26

CD26是一种已知能结合腺苷脱氨酶和二肽基肽酶IV活性的T细胞活化抗原。CD26和CD3与固定化单克隆抗体交联可以传递共刺激信号，促进T细胞活化。我们早期的研究表明，CD26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。虽然这些发现提示了内化在CD26功能中的重要性，但CD26在其细胞质区域只有6个aa残基，没有已知的内吞作用基序。在本研究中，我们已经确定甘露糖6-磷酸/胰岛素样生长因子II受体（M6P/IGFIIR）是CD26的结合蛋白，并且CD26碳水化合物部分中的甘露糖6-磷酸（M6P）残基对这种结合至关重要。外周血T细胞的活化导致甘露糖6磷酸化CD26。此外，CD26与抗CD26抗体的交联不仅诱导了CD26的capping和内化，还诱导了CD26与M6P/IGFIIR的共定位。最后，CD26的内化和由CD26介导的共刺激诱导的T细胞增殖反应均被M6P抑制，但6-磷酸葡萄糖或1-磷酸甘露糖不受抑制。这些结果表明，交联后CD26的内化部分是由M6P/IGFIIR介导的，甘露糖6磷酸化CD26与M6P/IGFIIR之间的相互作用可能在CD26介导的T细胞共刺激信号传导中发挥重要作用。

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 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.