Comodulation of CXCR4 and CD26 in Human Lymphocytes

Abstract

We provide convergent and multiple evidence for a CD26/CXCR4 interaction. Thus, CD26 codistributes with CXCR4, and both coimmunoprecipitate from membranes of T (CD4 ؉ ) and B (CD4 ؊ ) cell lines. Upon induction with stromal cell-derived factor 1␣ (SDF-1␣), CD26 is cointernalized with CXCR4. CXCR4-mediated downregulation of CD26 is not induced by antagonists or human immunodeficiency virus (HIV)-1 gp120. SDF1␣؊mediated down-regulation of CD26 is not blocked by pertussis toxin but does not occur in cells expressing mutant CXCR4 receptors unable to internalize. Codistribution and cointernalization also occurs in peripheral blood lymphocytes. Since CD26 is a cell surface endopeptidase that has the capacity to cleave SDF-1␣, the CXCR4⅐CD26 complex is likely a functional unit in which CD26 may directly modulate SDF-1␣-induced chemotaxis and antiviral capacity. CD26 anchors adenosine deaminase (ADA) to the lymphocyte cell surface, and this interaction is blocked by HIV-1 gp120. Here we demonstrate that gp120 interacts with CD26 and that gp120-mediated disruption of ADA/CD26 interaction is a consequence of a first interaction of gp120 with a domain different from the ADA binding site. SDF-1␣ and gp120 induce the appearance of pseudopodia in which CD26 and CXCR4 colocalize and in which ADA is not present. The physical association of CXCR4 and CD26, direct or part of a supramolecular structure, suggests a role on the function of the immune system and the pathophysiology of HIV infection.

Involvement of SDF‐1α/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma

“…In addition, Herrara et al clearly showed a close relationship between the expression of CXCR4 and DPPIV/CD26 in lymphocytes. 23 It is possible that in the tumor cells, these 2 molecules cooperate functionally with respect to metastatic potential.…”

A CD26-Controlled Cell Surface Cascade for Regulation of T Cell Motility and Chemokine Signals

“…1 suggested that chemokines metabolized by CD26, such as CXCL12 and CCL5 (53,54,58), that cleave Nterminal dipeptides from various chemokines regulate the cell surface expression of CD91 and TSP-1 through CD26. Therefore, we examined the possible influence of the CD26 inhibitors diprotin A, KR 62436, and vildagliptin on the cell surface expression of TSP-1 in anti-CD3-activated lymphocytes using quantitative immunocytochemistry and SDS-PAGE of immunoprecipitated biotinylated cell surface proteins (Fig.…”

Heparan Sulfate/Heparin Oligosaccharides Protect Stromal Cell-derived Factor-1 (SDF-1)/CXCL12 against Proteolysis Induced by CD26/Dipeptidyl Peptidase IV

“…This oligosaccharide, which is found ubiquitously at the cell surface and in the extracellular matrix, consists of sulfated glucosamine and iduronic residues clustered in a series of domains of variable lengths and sulfation patterns separated by regions of low sulfation and relatively uniform structure (32). SDF-1 binds with high affinity (K d of 30 nM) to the sulfated regions of HS (called S-domains), and we have shown that amino acids Lys 24 and Lys 27 have a dominant role in the binding. In addition, residues Lys 1 , Arg 41 , and Lys 43 participate in the recog-nition process but are not strictly required for the interaction to take place (33).…”

“…The N-terminal domain of the chemokine SDF-1 was shown to be efficiently processed by a number of proteases, including matrix metalloproteinase (18), cathepsin G (19), elastase (20), and dipeptidyl peptidase IV (DPP IV)/CD26 (21)(22)(23). Interestingly, among these enzymes, CD26, a cell surface serine protease, co-distributes and co-immunoprecipitates with CXCR4, suggesting a functional relationship with SDF-1 (24). CD26 removes the N-terminal dipeptides from a number of proteins having either a Pro or an Ala residue in the penultimate position (25), a characteristic shared by several chemokines (26,27).…”