We generated a mouse line in which the src homology 2 domain–bearing protein tyrosine phosphatase (SHP)-2 binding site of gp130, tyrosine 759, was mutated to phenylalanine (gp130 F759/F759). The gp130 F759/F759 mice developed rheumatoid arthritis (RA)-like joint disease. The disease was accompanied by autoantibody production and accumulated memory/activated T cells and myeloid cells. Before the disease onset, the T cells were hyperresponsive and thymic selection and peripheral clonal deletion were impaired. The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130 F759/F759 T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation. Finally, we showed that disease development was dependent on lymphocytes. These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease.
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, a 110 kDa cell surface glycoprotein, exhibits dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5) enzyme activity and plays an important role in T cell co-stimulation. In the present study, the function of CD26/DPPIV in transendothelial migration was examined using beta-chemokines as chemoattractants. When soluble recombinant CD26 (sCD26/DPPIV+) was added to the transendothelial chemotaxis system, chemotactic migration of T cells toward RANTES was significantly enhanced. Addition of sCD26 to 50 ng/ml of RANTES enhanced the migratory response by a factor of two compared to RANTES alone, whereas mutant soluble CD26 (mCD26), lacking the DPPIV enzyme activity, had no enhancing effect on RANTES-induced T cell migration. In the process of analyzing the mechanisms of the enhancement of T cell migration by sCD26, we showed that RANTES was cleaved by sCD26 under physiologic conditions at the precise site characteristic of its enzyme specificity. However, synthesized RANTES which lacks two N-terminal amino acids showed a chemotactic activity equivalent to full-length RANTES on T cells. Furthermore, addition of sCD26 showed enhancement of T cell migration induced by both forms of RANTES. In contrast to T cells, the truncated RANTES is inactive in chemotaxis of purified monocytes and supplement of sCD26 but not mCD26 reduced the migratory response of monocytes to RANTES. These results suggest that CD26/DPPIV differentially regulate the chemotactic response of T cells and monocytes to RANTES.
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