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*
Pulmonary Center, Boston University School of Medicine, Boston, MA 02118;
Department of Pharmacology, Utrecht University, Utrecht, The Netherlands; and
Washington and Jefferson College, Washington, PA 15301
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-1
(MIP-1) 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-1
(SDF-1)/CXCR4-induced chemotaxis; however, unlike MIP-1/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-1 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-1/CCR5 responses requires
p56lck enzymatic activity. IL-16/CD4 inhibition
of SDF-1/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.
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