Comodulation of CXCR4 and CD26 in Human Lymphocytes

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 1α (SDF-1α), CD26 is cointernalized with CXCR4. CXCR4-mediated down-regulation of CD26 is not induced by antagonists or human immunodeficiency virus (HIV)-1 gp120. SDF-1α−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-1α, the CXCR4·CD26 complex is likely a functional unit in which CD26 may directly modulate SDF-1α-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-1α 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. 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 1α (SDF-1α), CD26 is cointernalized with CXCR4. CXCR4-mediated down-regulation of CD26 is not induced by antagonists or human immunodeficiency virus (HIV)-1 gp120. SDF-1α−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-1α, the CXCR4·CD26 complex is likely a functional unit in which CD26 may directly modulate SDF-1α-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-1α 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. human immunodeficiency virus adenosine deaminase CXC chemokine receptor stromal-derived factor fluorescein isothiocyanate tetramethylrhodamine isothiocyanate monoclonal antibody phosphate-buffered saline phorbol 12-myristate 13-acetate CD26 is a widely distributed lymphocyte activation antigen that displays dipeptidyl peptidase IV activity in its extracellular domain. The role of CD26 in HIV1infection has been controversial. Its postulated role as coreceptor for HIV entry (1Callebaut C. Krust B. Jacotot E. Hovanessian A.G. Science. 1993; 262: 2045-2050Crossref PubMed Scopus (207) Google Scholar) was rapidly contested (2Broder C.C. Nussbaum O. Gutheil W.G. Bachovchin W.W. Berger E.A. Science. 1994; 264: 1156-1165Crossref PubMed Scopus (48) Google Scholar, 3Morimoto C. Lord C.I. Zhang C. Duke-Cohan J.S. Letvin N.L. Schlossman S.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9960-9964Crossref PubMed Scopus (73) Google Scholar). However, it has been more recently shown that the expression of CD26 may modulate HIV infection by direct effects of dipeptidyl peptidase IV activity on the antiviral activity of several chemokines or by unknown mechanisms independent of peptidase activity (4Proost P. Struyf S. Schols D. Durinx C. Wuyts A. Lenaerts J.P. De Clercq E. De Meester I. Van Damme J. FEBS Lett. 1998; 432: 73-76Crossref PubMed Scopus (179) Google Scholar, 5Oravecz T. Roderiquez G. Koffi J. Wang J. Ditto M. Bou-Habib D.C. Lusso P. Norcross M.A. Nat. Med. 1995; 1: 919-926Crossref PubMed Scopus (61) Google Scholar, 6Callebaut C. Jacotot E. Blanco J. Krust B. Hovanessian A.G. Exp. Cell Res. 1998; 241: 352-362Crossref PubMed Scopus (22) Google Scholar, 7Ohtsuki T. Hosono O. Kobayashi H. Munakata Y. Souta A. Shioda T. Morimoto C. FEBS Lett. 1998; 431: 236-240Crossref PubMed Scopus (57) Google Scholar).In fact, CD26 can cleave out NH2-terminal dipeptides from a protein with either l-proline or l-alanine at the penultimate position and several chemokines can be processed by CD26 (see Ref. 8De Meester I. Korom S. Van Damme J. Scharpé S. Immunol. Today. 1999; 20: 367-375Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar for review). For some chemokines proteolysis by CD26 does not affect the physiological activity. In contrast, truncation of RANTES (regulated on activation normal T cell expressed and secreted) by CD26 leads to higher receptor selectivity and anti-HIV activity (9Oravecz T. Pall M. Roderiquez G. Gorrell M.D. Ditto M. Nguyen N.Y. Boykins R. Unsworth E. Norcross M.A. J. Exp. Med. 1997; 186: 1865-1872Crossref PubMed Scopus (317) Google Scholar,10Proost P. de Meester I. Schols D. Struyf S. Lambeir A.-M. Wuyts A. Opdenakker G. De Clercq E. Scharpé S. van Damme J. J. Biol. Chem. 1998; 273: 7222-7227Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). Stromal cell-derived factor 1α (SDF-1α) also loses the NH2-terminal Lys-Pro dipeptide by the action of CD26. This processing significantly reduces the chemotactic and anti-HIV-1 activity of SDF-1α (4Proost P. Struyf S. Schols D. Durinx C. Wuyts A. Lenaerts J.P. De Clercq E. De Meester I. Van Damme J. FEBS Lett. 1998; 432: 73-76Crossref PubMed Scopus (179) Google Scholar, 11Shioda T. Kato H. Ohnishi Y. M. H. Kato A. Y. H. T. A. A. Morimoto C. Y. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google its CD26 interacts with Thus, the of Morimoto has that CD26 to a protein Y. E. T. Schlossman S.F. Morimoto C. J. Immunol. Google Scholar) and adenosine deaminase J. T. Y. Schlossman S.F. Morimoto C. Science. 1993; PubMed Scopus Google which is a protein that also on the surface of D. E. R. J. PubMed Scopus Google Scholar). has been shown that the binding of ADA to CD26 is by HIV-1 and by the with in the This is by the of the gp120 protein and occurs in human T and B cell by a by and CXCR4 expression A. Blanco J. C. Jacotot E. C. Hovanessian A.G. R. J. Immunol. 1997; Google Scholar, J. A. C. C. Hovanessian A.G. R. FEBS Lett. PubMed Scopus Google the functional dipeptidyl peptidase IV activity of CD26 and CXCR4, and the role of CXCR4 in gp120-mediated of ADA binding to CD26, we the of on the surface of human lymphocytes. In this we evidence of a and of CD26 and CXCR4. the is a of cell surface by the action of gp120 or SDF-1α, which is the of CXCR4. of CXCR4 and CD26 also cell surface this we demonstrate for the first that CD26 and CXCR4 in from human blood and also in T and B cell lines. The CXCR4 SDF-1α has the is at the which is a for of dipeptidyl peptidase IV activity of CD26. has been that SDF-1α can be processed by CD26 (4Proost P. Struyf S. Schols D. Durinx C. Wuyts A. Lenaerts J.P. De Clercq E. De Meester I. Van Damme J. FEBS Lett. 1998; 432: 73-76Crossref PubMed Scopus (179) Google Scholar, T. Pall M. Roderiquez G. Gorrell M.D. Ditto M. Nguyen N.Y. Boykins R. Unsworth E. Norcross M.A. J. Exp. Med. 1997; 186: 1865-1872Crossref PubMed Scopus (317) Google Scholar, 11Shioda T. Kato H. Ohnishi Y. M. H. Kato A. Y. H. T. A. A. Morimoto C. Y. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google S. Munakata Y. H. Hosono O. Schlossman S.F. Morimoto C. Immunol. 1999; PubMed Scopus Google Scholar). the complex is likely a functional unit in which the expression of CD26 on the cell surface may modulate SDF-1α-induced Since SDF-1α is a antiviral C.C. M. H. C. I. J. PubMed Scopus Google Scholar, E. A. C. O. I. M. M. B. PubMed Scopus Google the expression of CD26 can also modulate the activity of this of CXCR4 of that SDF-1α the cointernalization of CXCR4 and CD26 in cells and is also The SDF-1α-induced of the CD26/CXCR4 was not as we that the of expression of both on the cell surface with SDF-1α in but also in The and physiological of CD26/CXCR4 cointernalization was by the of in the of the in and in cell lines. The cells expressing a chemokine receptor the part also a to the of the interaction. In fact, the of the which is to down-regulation of CXCR4, also of CD26. that of with chemokines or that protein leads to the of CXCR4 and CD26, the as we for cell surface J. C. R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). SDF-1α-induced of CXCR4 is by A. S. O. J. M. P. M. J. Exp. Med. 1997; 186: PubMed Scopus Google Scholar). to the of the cointernalization by and by suggests that of CXCR4 and CD26 the by a of chemokine the of the the cell is of CXCR4 is distributed the which with the for this chemokine In contrast, CD26 is in that the of the the cointernalization different of CXCR4 is not by A. S. O. J. M. P. M. J. Exp. Med. 1997; 186: PubMed Scopus Google Scholar). The in the of pertussis toxin that of does not the This is evidence for a that the SDF-1α-induced of the this is the of cointernalization of a receptor and the that the for the receptor J. C. R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In of the of and of is Thus, in to of CD26 to SDF-1α (4Proost P. Struyf S. Schols D. Durinx C. Wuyts A. Lenaerts J.P. De Clercq E. De Meester I. Van Damme J. FEBS Lett. 1998; 432: 73-76Crossref PubMed Scopus (179) Google Scholar, 7Ohtsuki T. Hosono O. Kobayashi H. Munakata Y. Souta A. Shioda T. Morimoto C. FEBS Lett. 1998; 431: 236-240Crossref PubMed Scopus (57) Google Scholar). the of the be for the of in of CD26 with CXCR4 a of of CXCR4 with the shown it has been that peripheral blood SDF-1α expression of CXCR4 and CD26. This can be a consequence of a higher to SDF-1α from but it a cointernalization of CD26 and CXCR4 (see S. J. 1998; PubMed Google Scholar) that in peripheral blood cells the of gp120 of and CXCR4 with the M. D. S. U. Immunol. 1997; PubMed Scopus Google Scholar) that gp120 from the HIV-1 the of with some CD26 We demonstrate that that the gp120 the in T of pseudopodia in which the virus the the coreceptor CXCR4, and the CD26 the of and chemokine receptors in the of HIV entry has been the role of CD26 in this is not of A. Blanco J. C. Jacotot E. C. Hovanessian A.G. R. J. Immunol. 1997; Google Scholar) the of the binding ADA to the CD26 by HIV-1 gp120 and that gp120 the ADA binding of CD26. gp120 binding of ADA to CD26 in a J. A. C. C. Hovanessian A.G. R. FEBS Lett. PubMed Scopus Google Scholar). is that gp120 ADA binding to CD26 in cells of the of CXCR4. the (see Ref. J. A. C. C. Hovanessian A.G. R. FEBS Lett. PubMed Scopus Google Scholar) that gp120 has to to CXCR4 to its interaction with CD26 and the disruption of the ADA/CD26 interaction. In this we the of ADA binding to CD26, but we also demonstrate that gp120 the of ADA to CD26, and this in the expression of cell surface CD26 that gp120 and ADA a binding in CD26. shown in the gp120 was the some protein cell surface ADA from CD26. However, cells the with a the and the cell surface ADA was be that cell protein or to the of a gp120 binding domain in CD26 from the ADA binding site. This that the gp120-mediated of ADA to to CD26 be a consequence of a first interaction of gp120 with a in CD26. We and a different from ADA binding that the binding of gp120. in CD26 cells with the gp120. with the of interaction of gp120 with CD26 at different from the ADA binding and also a of cell surface CD26 by the protein of CXCR4 and CD26 by SDF-1α, of pseudopodia in which ADA is not and the role of ADA in the and function of the immune system R. A. C. Blanco J. Immunol. 1998; PubMed Scopus Google Scholar) that the and the complex is for the of human lymphocytes. CD26 is a widely distributed lymphocyte activation antigen that displays dipeptidyl peptidase IV activity in its extracellular domain. The role of CD26 in HIV1infection has been controversial. Its postulated role as coreceptor for HIV entry (1Callebaut C. Krust B. Jacotot E. Hovanessian A.G. Science. 1993; 262: 2045-2050Crossref PubMed Scopus (207) Google Scholar) was rapidly contested (2Broder C.C. Nussbaum O. Gutheil W.G. Bachovchin W.W. Berger E.A. Science. 1994; 264: 1156-1165Crossref PubMed Scopus (48) Google Scholar, 3Morimoto C. Lord C.I. Zhang C. Duke-Cohan J.S. Letvin N.L. Schlossman S.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9960-9964Crossref PubMed Scopus (73) Google Scholar). However, it has been more recently shown that the expression of CD26 may modulate HIV infection by direct effects of dipeptidyl peptidase IV activity on the antiviral activity of several chemokines or by unknown mechanisms independent of peptidase activity (4Proost P. Struyf S. Schols D. Durinx C. Wuyts A. Lenaerts J.P. De Clercq E. De Meester I. Van Damme J. FEBS Lett. 1998; 432: 73-76Crossref PubMed Scopus (179) Google Scholar, 5Oravecz T. Roderiquez G. Koffi J. Wang J. Ditto M. Bou-Habib D.C. Lusso P. Norcross M.A. Nat. Med. 1995; 1: 919-926Crossref PubMed Scopus (61) Google Scholar, 6Callebaut C. Jacotot E. Blanco J. Krust B. Hovanessian A.G. Exp. Cell Res. 1998; 241: 352-362Crossref PubMed Scopus (22) Google Scholar, 7Ohtsuki T. Hosono O. Kobayashi H. Munakata Y. Souta A. Shioda T. Morimoto C. FEBS Lett. 1998; 431: 236-240Crossref PubMed Scopus (57) Google Scholar). In fact, CD26 can cleave out NH2-terminal dipeptides from a protein with either l-proline or l-alanine at the penultimate position and several chemokines can be processed by CD26 (see Ref. 8De Meester I. Korom S. Van Damme J. Scharpé S. Immunol. Today. 1999; 20: 367-375Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar for review). For some chemokines proteolysis by CD26 does not affect the physiological activity. In contrast, truncation of RANTES (regulated on activation normal T cell expressed and secreted) by CD26 leads to higher receptor selectivity and anti-HIV activity (9Oravecz T. Pall M. Roderiquez G. Gorrell M.D. Ditto M. Nguyen N.Y. Boykins R. Unsworth E. Norcross M.A. J. Exp. Med. 1997; 186: 1865-1872Crossref PubMed Scopus (317) Google Scholar,10Proost P. de Meester I. Schols D. Struyf S. Lambeir A.-M. Wuyts A. Opdenakker G. De Clercq E. Scharpé S. van Damme J. J. Biol. Chem. 1998; 273: 7222-7227Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). Stromal cell-derived factor 1α (SDF-1α) also loses the NH2-terminal Lys-Pro dipeptide by the action of CD26. This processing significantly reduces the chemotactic and anti-HIV-1 activity of SDF-1α (4Proost P. Struyf S. Schols D. Durinx C. Wuyts A. Lenaerts J.P. De Clercq E. De Meester I. Van Damme J. FEBS Lett. 1998; 432: 73-76Crossref PubMed Scopus (179) Google Scholar, 11Shioda T. Kato H. Ohnishi Y. M. H. Kato A. Y. H. T. A. A. Morimoto C. Y. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). its CD26 interacts with Thus, the of Morimoto has that CD26 to a protein Y. E. T. Schlossman S.F. Morimoto C. J. Immunol. Google Scholar) and adenosine deaminase J. T. Y. Schlossman S.F. Morimoto C. Science. 1993; PubMed Scopus Google which is a protein that also on the surface of D. E. R. J. PubMed Scopus Google Scholar). has been shown that the binding of ADA to CD26 is by HIV-1 and by the with in the This is by the of the gp120 protein and occurs in human T and B cell by a by and CXCR4 expression A. Blanco J. C. Jacotot E. C. Hovanessian A.G. R. J. Immunol. 1997; Google Scholar, J. A. C. C. Hovanessian A.G. R. FEBS Lett. PubMed Scopus Google Scholar). the functional dipeptidyl peptidase IV activity of CD26 and CXCR4, and the role of CXCR4 in gp120-mediated of ADA binding to CD26, we the of on the surface of human lymphocytes. In this we evidence of a and of CD26 and CXCR4. the is a of cell surface by the action of gp120 or SDF-1α, which is the of CXCR4. of CXCR4 and CD26 also cell surface this we demonstrate for the first that CD26 and CXCR4 in from human blood and also in T and B cell lines. The CXCR4 SDF-1α has the is at the which is a for of dipeptidyl peptidase IV activity of CD26. has been that SDF-1α can be processed by CD26 (4Proost P. Struyf S. Schols D. Durinx C. Wuyts A. Lenaerts J.P. De Clercq E. De Meester I. Van Damme J. FEBS Lett. 1998; 432: 73-76Crossref PubMed Scopus (179) Google Scholar, T. Pall M. Roderiquez G. Gorrell M.D. Ditto M. Nguyen N.Y. Boykins R. Unsworth E. Norcross M.A. J. Exp. Med. 1997; 186: 1865-1872Crossref PubMed Scopus (317) Google Scholar, 11Shioda T. Kato H. Ohnishi Y. M. H. Kato A. Y. H. T. A. A. Morimoto C. Y. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google S. Munakata Y. H. Hosono O. Schlossman S.F. Morimoto C. Immunol. 1999; PubMed Scopus Google Scholar). the complex is likely a functional unit in which the expression of CD26 on the cell surface may modulate SDF-1α-induced Since SDF-1α is a antiviral C.C. M. H. C. I. J. PubMed Scopus Google Scholar, E. A. C. O. I. M. M. B. PubMed Scopus Google the expression of CD26 can also modulate the activity of this of CXCR4 of that SDF-1α the cointernalization of CXCR4 and CD26 in cells and is also The SDF-1α-induced of the CD26/CXCR4 was not as we that the of expression of both on the cell surface with SDF-1α in but also in The and physiological of CD26/CXCR4 cointernalization was by the of in the of the in and in cell lines. The cells expressing a chemokine receptor the part also a to the of the interaction. In fact, the of the which is to down-regulation of CXCR4, also of CD26. that of with chemokines or that protein leads to the of CXCR4 and CD26, the as we for cell surface J. C. R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). SDF-1α-induced of CXCR4 is by A. S. O. J. M. P. M. J. Exp. Med. 1997; 186: PubMed Scopus Google Scholar). to the of the cointernalization by and by suggests that of CXCR4 and CD26 the by a of chemokine the of the the cell is of CXCR4 is distributed the which with the for this chemokine In contrast, CD26 is in that the of the the cointernalization different of CXCR4 is not by A. S. O. J. M. P. M. J. Exp. Med. 1997; 186: PubMed Scopus Google Scholar). The in the of pertussis toxin that of does not the This is evidence for a that the SDF-1α-induced of the this is the of cointernalization of a receptor and the that the for the receptor J. C. R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In of the of and of is Thus, in to of CD26 to SDF-1α (4Proost P. Struyf S. Schols D. Durinx C. Wuyts A. Lenaerts J.P. De Clercq E. De Meester I. Van Damme J. FEBS Lett. 1998; 432: 73-76Crossref PubMed Scopus (179) Google Scholar, 7Ohtsuki T. Hosono O. Kobayashi H. Munakata Y. Souta A. Shioda T. Morimoto C. FEBS Lett. 1998; 431: 236-240Crossref PubMed Scopus (57) Google Scholar). the of the be for the of in of CD26 with CXCR4 a of of CXCR4 with the shown it has been that peripheral blood SDF-1α expression of CXCR4 and CD26. This can be a consequence of a higher to SDF-1α from but it a cointernalization of CD26 and CXCR4 (see S. J. 1998; PubMed Google Scholar) that in peripheral blood cells the of gp120 of and CXCR4 with the M. D. S. U. Immunol. 1997; PubMed Scopus Google Scholar) that gp120 from the HIV-1 the of with some CD26 We demonstrate that that the gp120 the in T of pseudopodia in which the virus the the coreceptor CXCR4, and the CD26 the of and chemokine receptors in the of HIV entry has been the role of CD26 in this is not of A. Blanco J. C. Jacotot E. C. Hovanessian A.G. R. J. Immunol. 1997; Google Scholar) the of the binding ADA to the CD26 by HIV-1 gp120 and that gp120 the ADA binding of CD26. gp120 binding of ADA to CD26 in a J. A. C. C. Hovanessian A.G. R. FEBS Lett. PubMed Scopus Google Scholar). is that gp120 ADA binding to CD26 in cells of the of CXCR4. the (see Ref. J. A. C. C. Hovanessian A.G. R. FEBS Lett. PubMed Scopus Google Scholar) that gp120 has to to CXCR4 to its interaction with CD26 and the disruption of the ADA/CD26 interaction. In this we the of ADA binding to CD26, but we also demonstrate that gp120 the of ADA to CD26, and this in the expression of cell surface CD26 that gp120 and ADA a binding in CD26. shown in the gp120 was the some protein cell surface ADA from CD26. However, cells the with a the and the cell surface ADA was be that cell protein or to the of a gp120 binding domain in CD26 from the ADA binding site. This that the gp120-mediated of ADA to to CD26 be a consequence of a first interaction of gp120 with a in CD26. We and a different from ADA binding that the binding of gp120. in CD26 cells with the gp120. with the of interaction of gp120 with CD26 at different from the ADA binding and also a of cell surface CD26 by the protein of CXCR4 and CD26 by SDF-1α, of pseudopodia in which ADA is not and the role of ADA in the and function of the immune system R. A. C. Blanco J. Immunol. 1998; PubMed Scopus Google Scholar) that the and the complex is for the of human lymphocytes. In this we demonstrate for the first that CD26 and CXCR4 in from human blood and also in T and B cell lines. The CXCR4 SDF-1α has the is at the which is a for of dipeptidyl peptidase IV activity of CD26. has been that SDF-1α can be processed by CD26 (4Proost P. Struyf S. Schols D. Durinx C. Wuyts A. Lenaerts J.P. De Clercq E. De Meester I. Van Damme J. FEBS Lett. 1998; 432: 73-76Crossref PubMed Scopus (179) Google Scholar, T. Pall M. Roderiquez G. Gorrell M.D. Ditto M. Nguyen N.Y. Boykins R. Unsworth E. Norcross M.A. J. Exp. Med. 1997; 186: 1865-1872Crossref PubMed Scopus (317) Google Scholar, 11Shioda T. Kato H. Ohnishi Y. M. H. Kato A. Y. H. T. A. A. Morimoto C. Y. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google S. Munakata Y. H. Hosono O. Schlossman S.F. Morimoto C. Immunol. 1999; PubMed Scopus Google Scholar). the complex is likely a functional unit in which the expression of CD26 on the cell surface may modulate SDF-1α-induced Since SDF-1α is a antiviral C.C. M. H. C. I. J. PubMed Scopus Google Scholar, E. A. C. O. I. M. M. B. PubMed Scopus Google the expression of CD26 can also modulate the activity of this of CXCR4 of The that SDF-1α the cointernalization of CXCR4 and CD26 in cells and is also The SDF-1α-induced of the CD26/CXCR4 was not as we that the of expression of both on the cell surface with SDF-1α in but also in The and physiological of CD26/CXCR4 cointernalization was by the of in the of the in and in cell lines. The cells expressing a chemokine receptor the part also a to the of the interaction. In fact, the of the which is to down-regulation of CXCR4, also of CD26. that of with chemokines or that protein leads to the of CXCR4 and CD26, the as we for cell surface J. C. R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). SDF-1α-induced of CXCR4 is by A. S. O. J. M. P. M. J. Exp. Med. 1997; 186: PubMed Scopus Google Scholar). to the of the cointernalization by and by suggests that of CXCR4 and CD26 the by a of chemokine the of the the cell is of CXCR4 is distributed the which with the for this chemokine In contrast, CD26 is in that the of the the cointernalization different of CXCR4 is not by A. S. O. J. M. P. M. J. Exp. Med. 1997; 186: PubMed Scopus Google Scholar). The in the of pertussis toxin that of does not the This is evidence for a that the SDF-1α-induced of the this is the of cointernalization of a receptor and the that the for the receptor J. C. R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In of the of and of is Thus, in to of CD26 to SDF-1α (4Proost P. Struyf S. Schols D. Durinx C. Wuyts A. Lenaerts J.P. De Clercq E. De Meester I. Van Damme J. FEBS Lett. 1998; 432: 73-76Crossref PubMed Scopus (179) Google Scholar, 7Ohtsuki T. Hosono O. Kobayashi H. Munakata Y. Souta A. Shioda T. Morimoto C. FEBS Lett. 1998; 431: 236-240Crossref PubMed Scopus (57) Google Scholar). the of the be for the of in of CD26 with CXCR4 a of of CXCR4 with the shown it has been that peripheral blood SDF-1α expression of CXCR4 and CD26. This can be a consequence of a higher to SDF-1α from but it a cointernalization of CD26 and CXCR4 (see S. J. 1998; PubMed Google Scholar) that in peripheral blood cells the of gp120 of and CXCR4 with the M. D. S. U. Immunol. 1997; PubMed Scopus Google Scholar) that gp120 from the HIV-1 the of with some CD26 We demonstrate that that the gp120 the in T of pseudopodia in which the virus the the coreceptor CXCR4, and the CD26 the of and chemokine receptors in the of HIV entry has been the role of CD26 in this is not of A. Blanco J. C. Jacotot E. C. Hovanessian A.G. R. J. Immunol. 1997; Google Scholar) the of the binding ADA to the CD26 by HIV-1 gp120 and that gp120 the ADA binding of CD26. gp120 binding of ADA to CD26 in a J. A. C. C. Hovanessian A.G. R. FEBS Lett. PubMed Scopus Google Scholar). is that gp120 ADA binding to CD26 in cells of the of CXCR4. the (see Ref. J. A. C. C. Hovanessian A.G. R. FEBS Lett. PubMed Scopus Google Scholar) that gp120 has to to CXCR4 to its interaction with CD26 and the disruption of the ADA/CD26 interaction. In this we the of ADA binding to CD26, but we also demonstrate that gp120 the of ADA to CD26, and this in the expression of cell surface CD26 that gp120 and ADA a binding in CD26. shown in the gp120 was the some protein cell surface ADA from CD26. However, cells the with a the and the cell surface ADA was be that cell protein or to the of a gp120 binding domain in CD26 from the ADA binding site. This that the gp120-mediated of ADA to to CD26 be a consequence of a first interaction of gp120 with a in CD26. We and a different from ADA binding that the binding of gp120. in CD26 cells with the gp120. with the of interaction of gp120 with CD26 at different from the ADA binding and also a of cell surface CD26 by the protein gp120. of CXCR4 and CD26 by SDF-1α, of pseudopodia in which ADA is not and the role of ADA in the and function of the immune system R. A. C. Blanco J. Immunol. 1998; PubMed Scopus Google Scholar) that the and the complex is for the of human lymphocytes. We the from and and from