The strength of the chemotactic response to a CCR5 binding chemokine is determined by the level of cell surface CCR5 density.
We have shown that the intensity of expression of the C-C chemokine receptor CCR5 at the single CD4(+) cell level strongly determines the efficiency of its function as a coreceptor for human immunodeficiency virus type 1. By analogy, we examined if the number of CCR5 molecules at the cell surface might determine its chemotactic response to CCR5 ligands. To test this hypothesis, we measured by flow cytometry the migration of primary human T cells towards the CCR5-binding chemokine CCL5 in vitro. First, we observed a dose-dependent blockage of this migration exerted by an anti-CCR5 monoclonal antibody. Second, we sorted peripheral blood mononuclear cells into five subpopulations expressing various cell surface CCR5 densities, and observed a correlation between the intensity of migration towards CCL5 and the level of CCR5 expression on these subpopulations. Third, we transduced CCR5(+) peripheral blood mononuclear cells with the CCR5 gene, and observed that the CCR5 over-expression induced an over-migration towards CCL5. Finally, we observed in healthy donors a correlation between the chemotactic response of peripheral blood CD8(+) T cell to CCL5 and their level of surface CCR5 expression. T-cell surface CCR5 density, which is constant over time for a given individual, but varies drastically among individuals, might therefore be an important personal determinant of T-cell migration in many biological situations where CCR5-binding chemokines play a role, such as graft rejection, T helper 1-mediated auto-immune diseases, and infectious diseases involving CCR5. Moreover, our data highlight the therapeutic potential of CCR5 antagonists in these situations.
Desmetz
Caroline
C
Institut de Génétique Humaine du CNRS UPR1142, Hôpital Saint Eloi, Montpellier, France.
Lin
Yea-Lih
YL
Mettling
Clément
C
Portalès
Pierre
P
Rabesandratana
Herisoa
H
Clot
Jacques
J
Corbeau
Pierre
P
D000911:Antibodies, Monoclonal / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D018946:Chemokine CCL5; D019742:Chemokines, CC / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D019713:Receptors, CCR5 / Q000097:blood* / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014161:Transduction, Genetic
D000911:Antibodies, Monoclonal; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D019742:Chemokines, CC; D019713:Receptors, CCR5