Reciprocal desensitization of CCR5 and CD4 is mediated by IL-16 and macrophage-inflammatory protein-1 beta, respectively.
The ability of HIV-1 gp120 to inhibit chemokine signaling prompted us to determine whether signaling through CD4 by a natural ligand, IL-16, could alter cellular responsiveness to chemokine stimulation. These studies demonstrate that IL-16/CD4 signaling in T lymphocytes results in a selective loss of macrophage-inflammatory protein (MIP)-1 beta/CCR5-induced chemotaxis. There was no effect on monocyte chemoattractant protein-2/CCR1, -2, or -3-induced chemotaxis. Desensitization of CCR5 by IL-16 required at least 10 min of pretreatment; no modulation of CCR5 expression was observed, nor was MIP-1 beta binding to CCR5 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 signal that results in desensitization of CCR5. The desensitization process is reciprocal and again selective, as prior CCR5 stimulation, but not CCR1, -2, or -3 stimulation, completely inhibits IL-16/CD4-induced T cell migration. Of interest, while p56lck enzymatic activity is not required for IL-16-induced migration, it was required for desensitization of CCR5. These studies indicate the existence of reciprocal receptor cross-desensitization between CD4 and CCR5 induced by two proinflammatory cytokines and suggest a selective relationship between the two receptors.
Mashikian
M V
MV
Pulmonary Center, Boston University School of Medicine, MA 02118, USA.
Ryan
T C
TC
Seman
A
A
Brazer
W
W
Center
D M
DM
Cruikshank
W W
WW
D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D054407:Chemokine CCL4; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019410:Interleukin-16 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000502:physiology*; D019713:Receptors, CCR5 / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D018909:src Homology Domains / Q000276:immunology
D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; D054407:Chemokine CCL4; D007166:Immunosuppressive Agents; D019410:Interleukin-16; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D011994:Recombinant Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)