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

• Published in: The Journal of experimental medicine Vol. 193; no. 6; pp. 713 - 726
• Main Authors: Huang, D R, Wang, J, Kivisakk, P, Rollins, B J, Ransohoff, R M
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 19.03.2001
• Subjects: Amino Acid Sequence; Animals; CD11 Antigens - genetics; CD3 Complex - genetics; CD4 Antigens - genetics; CD8 Antigens - genetics; Cell Division; Central Nervous System - metabolism; Central Nervous System - pathology; Chemokine CCL2 - genetics; Chemokine CCL2 - immunology; Chemokine CCL4; Chemokine CCL7; Chemokine CCL8; Chemokine CXCL10; Chemokines, CXC - biosynthesis; Cytokines; Encephalomyelitis, Autoimmune, Experimental - immunology; Gene Expression; Immunity, Innate; Interferon-gamma - biosynthesis; Interferon-gamma - genetics; Interleukin-10 - biosynthesis; Interleukin-10 - genetics; Interleukin-4 - biosynthesis; Interleukin-4 - genetics; Macrophage Inflammatory Proteins - biosynthesis; Macrophages - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Monocyte Chemoattractant Proteins - genetics; Myelin Proteins; Myelin Proteolipid Protein - pharmacology; Myelin-Associated Glycoprotein - pharmacology; Myelin-Oligodendrocyte Glycoprotein; Original; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; Th1 Cells - immunology; Up-Regulation
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.193.6.713

Monocyte chemoattractant protein (MCP)-1 plays a critical role in innate immunity by directing the migration of monocytes into inflammatory sites. Recent 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 function. Studies in a Th1-dependent animal model, experimental autoimmune encephalomyelitis (EAE), showed that MCP-1 was highly expressed in the central nervous system (CNS) of affected rodents, and MCP-1 antibodies could block relapses of the disease. Mice deficient for the major MCP-1 receptor, CC chemokine receptor (CCR)2, did not develop EAE after active immunization but generated effector cells that could transfer the disease to naive wild-type recipients. We analyzed EAE in mice deficient for MCP-1 to define the relevant ligand for 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 after active immunization, with drastically impaired recruitment of macrophages to the CNS, yet able to generate effector T cells that transferred severe disease to naive wild-type recipients. By contrast, adoptive transfer of primed T cells from wild-type mice into naive MCP-1-null recipients did not mediate clinical EAE. On the SJL background, disruption of the MCP-1 gene produced a milder EAE phenotype with diminished relapses that mimicked previous findings using anti-MCP-1 antibodies. There was no compensatory upregulation of MCP-2, MCP-3, or MCP-5 in MCP-1-null mice with EAE. These results indicated that MCP-1 is the major CCR2 ligand in mice with EAE, and provided an opportunity to define the role of MCP-1 in EAE. Compared with wild-type littermates, MCP-1-/- mice exhibited reduced expression of interferon gamma in draining lymph node and CNS and increased antigen-specific immunoglobulin G1 antibody production. Taken together, these data demonstrate that MCP-1 is crucial for Th1 immune responses in EAE induction and that macrophage recruitment to the inflamed CNS target organ is required for primed T cells to execute a Th1 effector program in EAE.