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 de termine whether signaling through CD4 by a natural ligand, IL-16, could alt er cellular responsiveness to chemokine stimulation. These studies demonstr ate that IL-16/CD4 signaling in T lymphocytes results in a selective loss o f macrophage-inflammatory protein (MIP)-1 beta/CCR5-induced chemotaxis, The re was no effect on monocyte chemoattractant protein-2/CCR1, -2, or 3-induc ed 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 t o express native or mutated forms of CD4, it was determined that IL-16/CD4 induces a p56(lck)-dependent signal that results in desensitization of CCR5 , The desensitization process is reciprocal and again selective, as prior C CR5 stimulation, but not CCR1, -2, or -3 stimulation, completely inhibits I L-16/CD4-induced T cell migration. Of interest, while p56(lck) enzymatic ac tivity is not required for IL-16-induced migration, it was required for des ensitization of CCR5, These studies indicate the existence of reciprocal re ceptor cross-desensitization between CD4 and CCR5 induced by two proinflamm atory cytokines and suggest a selective relationship between the two recept ors.