The responses of lymphocytes to six CC chemokines–MCP-1, MCP-2, MCP-3, MIP-1α, MIP-1β, and RANTES–were studied using cloned human CD4+ and CD8+ T cells. All CC chemokines tested induced migration of both types of lymphocytes, whereas two CXC chemokines used as controls, IL-8 and IP-10, were inactive. The monocyte chemotactic proteins (MCP-1, MCP-2, and MCP-3) showed a typically bimodal concentration dependence, and were considerably more effective than MIP-1α, MIP-10, or RANTES. All CC chemokines also induced a rapid and transient rise in cytosolic free Ca2+ in either type of T cell. The rise was prevented by Bordetella pertussis toxin treatment, indicating that G-protein-coupled receptors are involved in signaling. It was most pronounced with MCP-1 and MCP-3, which is in agreement with the efficacy of these chemokines as chemoattractants. The responses to MCP-2, MIP-1α, MIP-1β, and RANTES were weaker, and no changes were obtained on stimulation with IL-8 or IP-10. Freshly isolated human blood lymphocytes were also tested, but neither migration nor Ca2+ changes were observed. Low numbers of high-affinity receptors for MCP-1 were found on CD4+ and CD8+ cells (Kd + and CD8+ T cells, the monocyte chemotactic proteins could play a major role in the recruitment of activated T lymphocytes.—Loetscher, P., Seitz, M., Clark-Lewis, I., Baggiolini, M., Moser, B. Monocyte chemotactic proteins MCP-1, MCP-2, and MCP-3 are major attractants for human CD4+ and CD8+ T lymphocytes. FASEB J. 8: 1055-1060; 1994.