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Severe disease, unaltered leukocyte migration, and reduced IFN-γ production in CXCR3 mice with experimental autoimmune encephalomyelitis

Journal of Immunology, ISSN: 0022-1767, Vol: 176, Issue: 7, Page: 4399-4409
2006
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Experimental autoimmune encephalomyelitis (EAE) is a CD4 Th1 T cell-mediated disease of the CNS, used to study certain aspects of multiple sclerosis. CXCR3, the receptor for CXCL10, CXCL9, and CXCL11, is preferentially expressed on activated Th1 T cells and has been proposed to govern the migration of lymphocytes into the inflamed CNS during multiple sclerosis and EAE. Unexpectedly, CXCL10-defitient mice were susceptible to EAE, leaving uncertain what the role of CXCR3 and its ligands might play in this disease model. In this study, we report that CXCR3 mice exhibit exaggerated severity of EAE compared with wild-type (CXCR3) littermate mice. Surprisingly, there were neither quantitative nor qualitative differences in CNS-infiltrating leukocytes between CXCR3 and CXCR3 mice with EAE. Despite these equivalent inflammatory infiltrates, CNS tissues from CXCR3 mice with EAE showed worsened blood-brain barrier disruption and more von Willebrand factor-immunoreactive vessels within inflamed spinal cords, as compared with CXCR3 mice. Spinal cords of CXCR3 mice with EAE demonstrated decreased levels of IFN-γ, associated with reduced indudble NO synthase immunoreactivity, and lymph node T cells from CXCR3 mice primed with MOG secreted less IFN-γ in Ag-driven recall responses than cells from CXCR3 animals. CXCR3 lymph node T cells also showed enhanced Ag-driven proliferation, which was reduced by addition of IFN-γ. Taken with prior findings, our data show that CXCL10 is the most relevant ligand for CXCR3 to EAE. CXCR3 does not govern leukocyte trafficking in EAE but modulates T cell IFN-γ production and downstream events that affect disease severity. Copyright © 2006 by The American Association of Immunologists, Inc.

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