title: Engagement of CD28 modulates CXC chemokine receptor 4 surface expression in both resting and CD3-stimulated CD4+ T cells.
abstract: Optimal CD4+ T cell activation requires the cooperation of multiple signaling pathways coupled to the TCR-CD3 complex and to the CD28 costimulatory molecule. In this study, we have investigated the expression of surface CXC chemokine receptor 4 (CXCR4) in enriched populations of CD4+ T PBL, stimulated with anti-CD3 and anti-CD28 mAbs, immobilized on plastic. Anti-CD3 alone induced a progressive down-regulation of surface CXCR4, accompanied by a significant decline in the entry of the HXB2 T cell line-tropic (X4-tropic) HIV-1 clone in CD4+ T cells. Of note, this effect was strictly dependent on the presence in culture of CD14+ monocytes. On the other hand, anti-CD28 alone induced a small but reproducible increase in the expression of surface CXCR4 as well as in the entry of HXB2 HIV-1 clone in resting CD4+ T cells. When the two mAbs were used in combination, anti-CD28 potently synergized with anti-CD3 in inducing the expression of CD69 activation marker and stimulating the proliferation of CD4+ T cells. On the other hand, anti-CD28 counteracted the CXCR4 down-modulation induced by anti-CD3. The latter effect was particularly evident when anti-CD28 was associated to suboptimal concentrations of anti-CD3. Because CXCR4 is the major coreceptor for the highly cytopathic X4-tropic HIV-1 strains, which preferentially replicate in proliferating CD4+ T cells, the ability of anti-CD28 to up-regulate the surface expression of CXCR4 in both resting and activated CD4+ T cells provides one relevant mechanism for the progression of HIV-1 disease.
authors.affiliation: Institute of Human Virology, University of Maryland, Baltimore, MD 21201, USA. secchier@umbi.umd.edu
authors.forename: P
authors.initials: P
authors.lastname: Secchiero
authors.forename: D
authors.initials: D
authors.lastname: Zella
authors.forename: S
authors.initials: S
authors.lastname: Curreli
authors.forename: P
authors.initials: P
authors.lastname: Mirandola
authors.forename: S
authors.initials: S
authors.lastname: Capitani
authors.forename: R C
authors.initials: RC
authors.lastname: Gallo
authors.forename: G
authors.initials: G
authors.lastname: Zauli
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D017252:CD3 Complex / Q000276:immunology / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology; D005110:Extracellular Space / Q000276:immunology; D015696:Gene Products, tat / Q000502:physiology; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D007399:Interphase / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D009000:Monocytes / Q000276:immunology; D019713:Receptors, CCR5 / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D015696:Gene Products, tat; D018950:Lipopolysaccharide Receptors; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D054322:tat Gene Products, Human Immunodeficiency Virus