Fulminant lymphocytic choriomeningitis virus-induced inflammation of the CNS involves a cytokine-chemokine-cytokine-chemokine cascade.
Intracerebral inoculation of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) normally results in fatal CD8+ T cell mediated meningoencephalitis. However, in CXCL10-deficient mice, the virus-induced CD8+ T cell accumulation in the neural parenchyma is impaired, and only 30-50% of the mice succumb to the infection. Similar results are obtained in mice deficient in the matching chemokine receptor, CXCR3. Together, these findings point to a key role for CXCL10 in regulating the severity of the LCMV-induced inflammatory process. For this reason, we now address the mechanisms regulating the expression of CXCL10 in the CNS of LCMV-infected mice. Using mice deficient in type I IFN receptor, type II IFN receptor, or type II IFN, as well as bone marrow chimeras expressing CXCL10 only in resident cells or only in bone marrow-derived cells, we analyzed the up-stream regulation as well as the cellular source of CXCL10. We found that expression of CXCL10 initially depends on signaling through the type I IFN receptor, while late expression and up-regulation requires type II IFN produced by the recruited CD8+ T cells. Throughout the infection, the producers of CXCL10 are exclusively resident cells of the CNS, and astrocytes are the dominant expressors in the neural parenchyma, not microglial cells or recruited bone marrow-derived cell types. These results are consistent with a model suggesting a bidirectional interplay between resident cells of the CNS and the recruited virus-specific T cells with astrocytes as active participants in the local antiviral host response.
Christensen
Jeanette E
JE
University of Copenhagen, Department of International Health, Immunology and Microbiology, Copenhagen, Denmark.
Simonsen
Stine
S
Fenger
Christina
C
Sørensen
Maria R
MR
Moos
Torben
T
Christensen
Jan P
JP
Finsen
Bente
B
Thomsen
Allan R
AR
D000818:Animals; D000956:Antigens, Viral / Q000502:physiology; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D006023:Glycoproteins / Q000502:physiology; D018836:Inflammation Mediators / Q000502:physiology*; D007276:Injections, Intraventricular; D007370:Interferon Type I / Q000502:physiology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000821:virology; D015854:Up-Regulation / Q000276:immunology; D014764:Viral Proteins / Q000502:physiology
D000956:Antigens, Viral; D054357:Chemokine CXCL10; D018925:Chemokines; C485433:Cxcl10 protein, mouse; D016207:Cytokines; D006023:Glycoproteins; D018836:Inflammation Mediators; D007370:Interferon Type I; D010446:Peptide Fragments; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus