Chemokines are a family of small-molecular-weight cytokines that induce chemotaxis and chemokinesis of leukocytes. These molecules are ligands for seven-transmembrane, G-protein-linked receptors and are known to activate integrins on the surface of leukocytes and other cells as well as induce a number of signaling events. They play a significant role in the migration of leukocytes from blood into tissue during inflammatory processes. We tested the role of chemokines in experimental autoimmune encephalomyelitis (EAE) and found that macrophage inflammatory protein-1alpha (MIP-1alpha) correlated with acute disease development, whereas monocyte chemotactic protein-1 (MCP-1) did not. In contrast, MCP-1 production in the central nervous system correlated with relapsing EAE development. Moreover, anti-MIP-1alpha, but not anti-MCP-1, inhibited development of acute but not relapsing EAE, whereas anti-MCP-1 significantly reduced the severity of relapsing EAE. To test the effects of chemokines on the differentiation of naive T cells, TCR transgenic splenic T cells (Tg+ T cells) from DO11.10 OVA TCR transgenic mice were used as a source of Th0 cells and were stimulated with specific anti-clonotypic monoclonal antibodies in the presence of MIP-1alpha, MCP-1, or controls. MIP-1alpha drove Th0 cells to differentiate to Th1, whereas MCP-1 drove Th0 cells to differentiate to Th2. Similarly, MCP-1, but not MIP-1alpha significantly inhibited the adoptive transfer of EAE when included in in vitro activation cultures, further suggesting a regulatory anti-inflammatory property. These results suggest a differential role for CC chemokines in the development and activation of T cells during autoimmune inflammatory diseases.