Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation

CD26 is a T cell activation antigen known to bind adenosine deaminase and h ave dipeptidyl peptidase IV activity. Cross-linking of CD26 and CD3 with im mobilized mAbs can deliver a costimulatory signal that contributes to T cel l activation. Our earlier studies revealed that cross-linking of CD26 induc es its internalization. the phosphorylation of a number of proteins involve d in the signaling pathway. and subsequent T cell proliferation. Although t hese findings suggest the importance of internalization in the function of CD26, CD26 has only 6 aa residues in its cytoplasmic region with no known m otif for endocytosis. In the present study, we have identified the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGFIIR) as a bindin g protein for CD26 and that mannose 6-phosphate (M6P) residues in the carbo hydrate moiety of CD26 are critical for this binding. Activation of periphe ral blood T cells results in the mannose 6 phosphorylation of CD26. In addi tion, the cross-linking of CD26 with an anti-CD26 antibody induces not only capping and internalization of CD26 but also colocalization of CD26 with M 6P/IGFIIR. Finally, both internalization of CD26 and the T cell proliferati ve response induced by CD26-mediated costimulation were inhibited by the ad dition of M6P, but not by glucose 6-phosphate or mannose l-phosphate. These results indicate that internalization of CD26 after crosslinking is mediat ed in part by MGP/IGFIIR and that the interaction between mannose 6-phospho rylated CD26 and M6P/IGFIIR may play an important role in CD26-mediated T c ell costimulatory signaling.