Desensitization of CXC Chemokine Receptor 4, Mediated by IL-16/CD4, Is Independent of p56 lck Enzymatic Activity

• Published in: The Journal of immunology (1950) 2000-12, Vol.165 (11), p.6356-6363
• Main Authors: Van Drenth, Charlotte, Jenkins, Ayana, Ledwich, Lindsey, Ryan, Thomas C., Mashikian, Margaret Vallen, Brazer, William, Center, David M., Cruikshank, William W.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.11.6356

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 p56lck 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-1β (MIP-1β) 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-1α (SDF-1α)/CXCR4-induced chemotaxis; however, unlike MIP-1β/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-1α 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 p56lck-dependent inhibitory signal for CXCR4, which is independent of its tyrosine catalytic activity. By contrast, IL-16/CD4 desensitization of MIP-1β/CCR5 responses requires p56lck enzymatic activity. IL-16/CD4 inhibition of SDF-1α/CXCR4 signals requires the presence of the Src homology 3 domain of p56lck 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.