Development of specific imuune regulatoly drugs by the cell surface molecules.

CD26是T细胞活化抗原，也已知与腺苷脱氨酶（ADA）结合，并具有二肽基肽酶IV （DPPIV）活性。CD26和CD3与固定的单克隆抗体交联可以传递第二种共刺激信号，并有助于T细胞活化。我们早期的研究表明，CD26的交联诱导了分子的内化，随后信号分子的酪氨酸磷酸化，并导致T细胞的增殖反应增强。尽管这些发现提示了内化在CD26功能中的重要性。CD26细胞质区只有6个氨基酸残基，没有已知的胞吞作用基序。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，CD26碳水化合物部分的甘露糖6-磷酸（M6P）残基对于CD26与M6P/IGFIIR的结合至关重要。在人外周血淋巴细胞中，T细胞活化导致甘露糖6磷酸化CD26。此外，CD26与抗CD26抗体的交联不仅诱导了CD26的封顶和内化，还诱导了CD26与M6P/IGFIIR的共定位。最后，添加M6P可抑制CD26交联内化和CD26介导的T细胞共刺激诱导的T细胞增殖，但不受葡萄糖- 6-磷酸或甘露糖- 1-磷酸抑制。这些结果表明甘露糖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 the T cell activation antigen and also known to bind the adenosine deaminase (ADA) and have a dipeptidyl peptidase IV (DPPIV) activity. Cross-linking of CD26 and CD3 with immobilized monoclonal antibodies can deliver a second costimulatory signal and contribute to T cell activation. Our earlier studies revealed that the cross-linking of CD26 induced internalization of the molecules, subsequent tyrosine phosphorylation of signaling molecules and resulted in an enhanced proliferating responses of T cells. Although these findings suggests the importance of internalization in the function of CD26. CD26 has only 6 amino acid residues in its cytoplasmic region with no known motif for endocytosis. In this study, we have identified the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGFIIR) as the binding protein for CD26, and the mannose 6-phosphate (M6P) residues in carbohydrate moiety of CD26 is critical for the binding between CD26 and M6P/IGFIIR. In human peripheral blood lymphocytes, T cell activation resulted in the mannose 6-phosphorylation of CD26. In addition, the cross-linking of CD26 with an anti-CD26 antibody induced not only capping and internalization of CD26 but also colocalization of CD26 with M6P/IGFIIR. Finally, internalization of CD26 by cross-linking and T cell proliferation induced by CD26 mediated T cell costimulation were inhibited by the addition of M6P, but not by the glucose 6-phosophate or mannose 1-phosphate. These results indicate that the interaction between mannose 6-phosphorylated CD26 and M6P/IGFIIR may play an important role in CD26-mediated T cell constimulatory signaling.