IFN-gamma shapes immune invasion of the central nervous system via regulation of chemokines.
Dynamic interplay between cytokines and chemokines directs trafficking of leukocyte subpopulations to tissues in autoimmune inflammation. We have examined the role of IFN-gamma in directing chemokine production and leukocyte infiltration to the CNS in experimental autoimmune encephalomyelitis (EAE). BALB/c and C57BL/6 mice are resistant to induction of EAE by immunization with myelin basic protein. However, IFN-gamma-deficient (BALB/c) and IFN-gammaR-deficient (C57BL/6) mice developed rapidly progressing lethal disease. Widespread demyelination and disseminated leukocytic infiltration of spinal cord were seen, unlike the focal perivascular infiltrates in SJL/J mice. Gr-1+ neutrophils predominated in CNS, and CD4+ T cells with an activated (CD69+, CD25+) phenotype and eosinophils were also present. RANTES and macrophage chemoattractant protein-1, normally up-regulated in EAE, were undetectable in IFN-gamma- and IFN-gammaR-deficient mice. Macrophage inflammatory protein-2 and T cell activation gene-3, both neutrophil-attracting chemokines, were strongly up-regulated. There was no induction of the Th2 cytokines, IL-4, IL-10, or IL-13. RNase protection assays and RT-PCR showed the prevalence of IL-2, IL-3, and IL-15, but no increase in IL-12p40 mRNA levels in IFN-gamma- or IFN-gammaR-deficient mice with EAE. Lymph node cells from IFN-gamma-deficient mice proliferated in response to myelin basic protein, whereas BALB/c lymph node cells did not. These findings show a regulatory role for IFN-gamma in EAE, acting on T cell proliferation and directing chemokine production, with profound implications for the onset and progression of disease.
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Neuroimmunology Unit, Montreal Neurological Institute, and Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
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Owens
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D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002417:Cattle; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D054402:Chemokine CCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019742:Chemokines, CC; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology; D009186:Myelin Sheath / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D054401:Receptors, CCR8; D017471:Receptors, Interferon / Q000235:genetics; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D000096743:Interferon gamma Receptor
D054402:Chemokine CCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D007371:Interferon-gamma; D004676:Myelin Basic Protein; D012333:RNA, Messenger; D054401:Receptors, CCR8; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C065971:CCL1 protein, human; C489319:Ccr8 protein, mouse; C404915:Cxcl2 protein, mouse