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Production in CXCR3–/– Mice with Experimental Autoimmune Encephalomyelitis1
* Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195;
Department of Immunology Research, Merck Research Laboratories, Rahway, NJ, 07065; and
Ina Sue Perlmutter Laboratory, Children’s Hospital and Harvard Medical School, Boston, MA 02115
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-deficient 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-
, associated with reduced inducible NO synthase immunoreactivity, and lymph node T cells from CXCR3–/– mice primed with MOG35–55 secreted less IFN- 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-. Taken with prior findings, our data show that CXCL10 is the most relevant ligand for CXCR3 in EAE. CXCR3 does not govern leukocyte trafficking in EAE but modulates T cell IFN- production and downstream events that affect disease severity.
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