REGULATION OF THE RECEPTOR SPECIFICITY AND FUNCTION OF THE CHEMOKINE RANTES (REGULATED ON ACTIVATION, NORMAL T-CELL EXPRESSED AND SECRETED)BY DIPEPTIDYL PEPTIDASE-IV (CD26)-MEDIATED CLEAVAGE

CD26 is a leukocyte activation marker that possesses dipeptidyl peptid ase IV activity but whose natural substrates and immunological functio ns have not been clearly defined. Several chemokines, including RANTES (regulated on activation, normal T cell expressed and secreted), have now been shown to be substrates for recombinant soluble human CD26. T he truncated RANTES(3-68) lacked the ability of native RANTES(1-68) to increase the cytosolic calcium concentration in human monocytes, but still induced this response in macrophages activated with macrophage c olony-stimulating factor. Analysis of chemokine receptor messenger RNA s and patterns of desensitization of chemokine responses showed that t he differential activity of the truncated molecule results from an alt ered receptor specificity. RANTES(3-68) showed a reduced activity, rel ative to that of RANTES(1-68), with cells expressing the recombinant C CR1 chemokine receptor, but retained the ability to stimulate CCR5 rec eptors and to inhibit the cytopathic effects of HIV-1. Our results ind icate that CD26-mediated processing together with cell activation-indu ced changes in receptor expression provides an integrated mechanism fo r differential cell recruitment and for the regulation of target cell specificity of RANTES, and possibly other chemokines.