title: Desensitization of CXC chemokine receptor 4, mediated by IL-16/CD4, is independent of p56lck enzymatic activity.
abstract: CCR5 and CXC chemokine receptor 4 (CXCR4) are coreceptors for CD4 as defined by HIV-1 glycoprotein (gp) 120 binding. Pretreatment of T cells with gp120 results in modulation of both CCR5 and CXCR4 responsiveness, which is dependent upon p56(lck) enzymatic activity. The recent findings that pretreatment of T cells with a natural CD4 ligand, IL-16, could alter cellular responsiveness to macrophage-inflammatory protein-1ss (MIP-1ss) stimulation, prompted us to investigate whether IL-16 could also alter CXCR4 signaling. These studies demonstrate that IL-16/CD4 signaling in T lymphocytes also results in loss of stromal derived factor-1alpha (SDF-1alpha)/CXCR4-induced chemotaxis; however, unlike MIP-1ss/CCR5, the effects were not reciprocal. There was no effect on eotaxin/CCR3-induced chemotaxis. Desensitization of CXCR4 by IL-16 required at least 10-15 min pretreatment; no modulation of CXCR4 expression was observed, nor was SDF-1alpha binding altered. Using murine T cell hybridomas transfected to express native or mutated forms of CD4, it was determined that IL-16/CD4 induces a p56(lck)-dependent inhibitory signal for CXCR4, which is independent of its tyrosine catalytic activity. By contrast, IL-16/CD4 desensitization of MIP-1ss/CCR5 responses requires p56(lck) enzymatic activity. IL-16/CD4 inhibition of SDF-1alpha/CXCR4 signals requires the presence of the Src homology 3 domain of p56(lck) and most likely involves activation of phosphatidylinositol-3 kinase. These studies indicate the mechanism of CXCR4 receptor desensitization induced by a natural ligand for CD4, IL-16, is distinct from the inhibitory effects induced by either gp120 or IL-16 on CCR5.
authors.affiliation: Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: C
authors.initials: C
authors.lastname: Van Drenth
authors.forename: A
authors.initials: A
authors.lastname: Jenkins
authors.forename: L
authors.initials: L
authors.lastname: Ledwich
authors.forename: T C
authors.initials: TC
authors.lastname: Ryan
authors.forename: M V
authors.initials: MV
authors.lastname: Mashikian
authors.forename: W
authors.initials: W
authors.lastname: Brazer
authors.forename: D M
authors.initials: DM
authors.lastname: Center
authors.forename: W W
authors.initials: WW
authors.lastname: Cruikshank
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002464:Cell Migration Inhibition; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D006825:Hybridomas; D019410:Interleukin-16 / Q000235:genetics / Q000502:physiology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D051379:Mice; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017154:Stromal Cells / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D018909:src Homology Domains / Q000276:immunology
chemical_list: D015704:CD4 Antigens; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019410:Interleukin-16; D019718:Receptors, CXCR4; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)