SummarySeveral studies have shown that CC chemokines attract T lymphocytes, and that CD45RO +, memory phenotype cells are considered to be the main responders. The results, however, have often been contradictory and the role of lymphocyte activation and proliferation has remained unclear. Using CD45RO + blood lymphocytes cultured under different stimulatory conditions, we have now studied chemotaxis as well as chemokine receptor expression. Expression of the RANTES/MIP-lc~ receptor (CC-CK1K1) and the MCP-1 receptor (CC-CKR2) was highly correlated with migration toward RANTES, MCP-1, and other CC chemokines, and was strictly dependent on the presence of IL-2 in the culture medium. Migration and receptor expression were rapidly downregulated when IL-2 was withdrawn, but were fully restored when IL-2 was added again. The effect oflL-2 could be partially mimicked by IL-4, IL-10, or IL-12, but not by IL-13, IFN',/, IL-1[3, TNF-el, or by exposure to anti-CD3, anti-CD28 or phytohemagglutinin. Activation of fully responsive lymphocytes through the TCP,./CD3 complex and CD28 antigen actually had the opposite effect. It rapidly downregulated receptor expression and consequent migration even in the presence of IL-2. In contrast to the effects on CC chemokine receptors, stimulation ofCD45ILO + T lymphocytes with IL-2 neither induced the expression of the CXC chemokine receptors, IL8-R1 and IL8-P-.2, nor chemotaxis to IL-8. The prominent role of IL-2 in CC chemokine responsiveness of lymphocytes suggests that IL-2-mediated expansion is a prerequisite for the recruitment of antigen-activated T cells into sites of immune and inflammatory reactions. Several chemokines of the CC subfamily are critically involved in the regulation of phagocyte and lymphocyte recruitment in many pathological situations (1, 2). The effects of CC chemokines on monocytes (3-5), basophil, and eosinophil leukocytes (6, 7) are well defined and generally accepted. The situation is more complex for lymphocytes. T lymphocytes were shown to migrate toward RANTES, the macrophage inflammatory proteins MIP-1 ot and MIP-lJ3 (8-10) and, more recently, to respond to the monocyte chemotactic proteins MCP-1, MCP-2, and MCP-3, which are highly effective on CD4 + and CD8 + T cells (11-13). All these CC chemokines induced a transient cytosolic free Ca 2+ rise in T cell clones, which was prevented by B. pertussis toxin (11) suggesting the involvement of G protein-coupled receptors (14). Neither Ca 2+ changes nor chemotaxis, however, were observed in freshly isolated blood lymphocytes, suggesting that activation is necessary.Several chemokine receptors were identified by cloning of their corresponding cDNAs from phagocyte-derived libraries (15)(16)(17)(18)(19)(20)(21)(22). CXC chemokine receptors are expressed primarily in neutrophils (15,16,23), whereas CC chemokine receptors (CC-CKR) 1 are generally found on other leukocytes (17)(18)(19)(20)(21)(22). No corresponding cDNA has been obtained from lymphocytes, however, and little is known about the expression of chemokin...