The ligands of CXC chemokine receptor 3, I-TAC, Mig, and IP10, are naturalantagonists for CCR3

Th1 and Th2 lymphocytes express a different repertoire of chemokine recepto rs (CCRs), CXCR3, the receptor for I-TAG (interferon-inducible T cell alpha -chemoattractant), Mig (monokine induced by gamma -interferon), and IP10 ( interferon-inducible protein 10), is expressed preferentially on Th1 cells, whereas CCR3, the receptor for eotaxin and several other CC chemokines, is characteristic of Th2 cells. While studying responses that are mediated by these two receptors, we found that the agonists for CXCR3 act as antagonis ts for CCR3. I-TAG, Mig, and IP10 compete for the binding of eotaxin to CCR 3-bearing cells and inhibit migration and Ca2+ changes induced in such cell s by stimulation with eotaxin, eotanin-2, MCP-S (monocyte chemottractant pr otein-2), MCP-S, MCP-4, and RANTES (regulated on activation normal T cell e xpressed and secreted). A hybrid chemokine generated by substituting the fi rst eight NH2-terminal residues of eotaxin with those of I-TAG bound CCR3 w ith higher affinity than eotaxin or I-TAG (3- and 10-fold, respectively). T he hybrid was 5-fold more potent than I-TAG as an inhibitor of eotaxin acti vity and was effective at concentrations as low as 5 nM. None of the antago nists described induced the internalization of CCR3, indicating that they l ack agonistic effects and thus qualify as pure antagonists. These results s uggest that chemokines that attract Th1 cells via CXCR3 can concomitantly b lock the migration of Th2 cells in response to CCR3 ligands, thus enhancing the polarization of T cell recruitment.