Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis

Monocyte chemoattractant protein (MCP)-1 plays a critical role in innate im munity by directing the migration of monocytes into inflammatory sites. Rec ent data indicated a function for this chemokine in adaptive immunity as a regulator of T cell commitment to T helper cell type 2 (Th2) effector funct ion. Studies in a Th1-dependent animal model, experimental autoimmune encep halomyelitis (EAE), showed that MCP-1 was highly expressed in the central n ervous system (CNS) of affected rodents, and MCP-1 antibodies could block r elapses of the disease. Mice deficient for the major MCP-1 receptor, CC che mokine receptor (CCR)2, did not develop EAE after active immunization but g enerated effector cells that could transfer the disease to naive wild-type recipients. We analyzed EAE in mice deficient for MCP-1 to define the relev ant ligand fur CCR2, which responds to murine MCP-1, MCP-2, MCP-3, and MCP- 5. We found that C57BL/6 MCP-1-null mice were markedly resistant to EAE aft er active immunization, with drastically impaired recruitment of macrophage s to the CNS, yet able to generate effector T cells that transferred severe disease to naive wild-type recipients. By contrast, adoptive transfer of p rimed T cells from wild-type mice into naive MCP-1-null recipients did riot mediate clinical EAE. On the SJL background, disruption of the MCP-1 gene produced a milder EAE phenotype with diminished relapses that mimicked prev ious findings using anti-MCP-l antibodies. There was no compensatory upregu lation of MCP-2, MCP-3, or MCP-5 ill MCP-l-null mice with EAE. These result s indicated that MCP-I is the major CCR2. ligand in mice with EAE, and prov ided an opportunity to define the role of MCP-1 in EAE, Compared with wild- type littermates, MCP-1(-/-) mice exhibited reduced expression of interfero n gamma in draining lymph node and CNS and increased antigen-specific immun oglobulin G1 antibody production. Taken together, these data demonstrate th at MCP-1 is crucial for Th1 immune responses in EAE induction and that macr ophage recruitment to the inflamed CNS target organ is required for primed T cells to execute a Th1 effector program in EAE.