Desensitization of CXC chemokine receptor 4, mediated by IL-16/CD4, is independent of p56(lck) enzymatic activity

CCR5 and CXC chemokine receptor 4 (CXCR4) are coreceptors for CD4 as define d by HIV-1 glycoprotein (gp) 120 binding. Pretreatment of T cells with gp12 0 results in modulation of both CCR5 and CXCR4 responsiveness, which is dep endent upon p56(lck) enzymatic activity, The recent findings that pretreatm ent of T cells with a natural CD4 ligand, IL-16, could alter cellular respo nsiveness to macrophage-inflammatory protein-1 beta (MIP-1 beta) stimulatio n, prompted us to investigate whether IL-16 could also alter CXCR4 signalin g. These studies demonstrate that IL-16/CD4 signaling in T lymphocytes also results in loss of stromal derived factor-1 alpha (SDF-1 alpha)/CXCR4-indu ced chemotaxis; however, unlike MIP-1 beta /CCR5, the effects were not reci procal. There was no effect on eotaxin/CCR3-induced chemotaxis. Desensitiza tion of CXCR4 by IL-16 required at least 10-15 min pretreatment; no modulat ion of CXCR4 expression was observed, nor was SDF-1 alpha binding altered. Using murine T cell hybridomas transfected to express native or mutated for ms of CD4, it was determined that IL-16/CD4 induces a p56(lck)-dependent in hibitory signal for CXCR4, which is independent of its tyrosine catalytic a ctivity, By contrast, IL-16/CD4 desensitization of MTP-1 beta /CCR5 respons es requires p56(lck) enzymatic activity. IL-16/CD4 inhibition of SDP-1 alph a /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 indu ced by a natural ligand for CD4, IL-16, is distinct from the inhibitory eff ects induced by either gp120 or IL-16 on CCR5.