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

Abstract

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-phosphate͞insulin-like growth factor II receptor (M6P͞IGFIIR) 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 M6P͞IGFIIR. 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 crosslinking is mediated in part by M6P͞IGFIIR and that the interaction between mannose 6-phosphorylated CD26 and M6P͞IGFIIR may play an important role in CD26-mediated T cell costimulatory signaling.T cell activation antigen CD26 is a multifunctional, 110-kDa cell surface glycoprotein (1, 2). Although constitutively expressed in the liver, intestine, and kidney, the CD26 expression level is tightly regulated on T cells and its density is markedly enhanced after T cell activation. In the resting state, CD26 is expressed on a subset of CD4 ϩ memory T cells, and this CD4 ϩ CD26 high T cell population has been shown to respond maximally to recall antigens (1, 2).CD26 has a dipeptidyl peptidase IV (DPPIV) activity in its extracellular domain that can cleave amino-terminal dipeptides with either proline or alanine in the penultimate position (3, 4). Recently, it has been reported that an amino-terminal truncation of RANTES (regulated on activation, normal T cell expressed and secreted) by CD26͞DPPIV provides a mechanism for regulation of its activity and target cell specificity (5-7). On the other hand, CD26 interacts, presumably via its extracellular domain, with CD45, a protein tyrosine-phosphatase (8). In addition, the extracellular domain of CD26 on T cells forms a complex with adenosine deaminase, which reduces the immunosuppressive activity of local adenosine by its catalytic removal (9-12). The most striking evidence for the importance of adenosine deaminase for immune function is that a defect in adenosine deaminase activity results in severe combined immunodeficiency disease in humans (13,14).CD26 is not only highly expressed on act...

CD26 up-regulates expression of CD86 on antigen-presenting cells by means of caveolin-1

“…9A) and by resting monocytes (20). Although it has been reported that the 300-kDa protein M6P͞IGF-IIR was linked with CD26 on the T cell surface to enhance CD26-mediated costimulation (8), no protein with a molecular mass of Ϸ300 kDa was detected by our purification method. An explanation may be that M6P͞IGF-IIR might compete with ADA to bind CD26 because we used CD26-ADA Sepharose bead columns to purify potential CD26-associated molecules.…”

“…Importantly, DPPIV enzyme activity is required for CD26-mediated T cell costimulation (7). More recently, we have shown that internalization of CD26 after crosslinking is mediated in part by the mannose-6-phosphate͞ insulin-like growth factor II receptor (M6P͞IGF-IIR), and that CD26-M6P͞IGFIIR interaction plays a role in CD26-induced T cell costimulation (8).…”

Degradation of Incretins and Modulation of Blood Glucose Levels by Periodontopathic Bacterial Dipeptidyl Peptidase 4

“…Furthermore, since hDPP4 is known as a multifunctional peptidase that not only functions with hydrolase but also is involved in T-cell activation, lymphocyte-epithelial cell adhesion, and the pericellular proteolysis of the extracellular matrix (49)(50)(51)(52), bacterial DPP4 might have additional roles in periodontopathic patients. In conclusion, we propose a novel molecular mechanism of periodontitis-diabetes interaction, in which periodontopathic bacterial DPP4 adversely impacts glycemic control.…”

The secreted glycoprotein CREG inhibits cell growth dependent on the mannose-6-phosphate/insulin-like growth factor II receptor

“…First, binding to the M6P/IGF2R could be required for proper localization of CREG. The receptor could concentrate CREG at the cell surface and promote an efficient interaction of CREG with another cell surface protein, as shown for uPAR (Nykjaer et al, 1998), or mediate internalization of CREG to localize it to its site of action, as shown for CD26 (Ikushima et al, 2000). The immunofluorescence data presented here In the second model, the binding of CREG to M6P/ IGF2R could alter receptor trafficking as shown for RA (Kang et al, 1998), and/or the binding to other ligands as shown for beta-galactosidase (MacDonald et al, 1988;Waheed et al, 1988;Kiess et al, 1990).…”