Efficient T-cell surveillance of the CNS requires expression of the CXC chemokine receptor 3.
T-cells play an important role in controlling viral infections inside the CNS. To study the role of the chemokine receptor CXCR3 in the migration and positioning of virus-specific effector T-cells within the brain, CXCR3-deficient mice were infected intracerebrally with lymphocytic choriomeningitis virus (LCMV). Analysis of the induction phase of the antiviral CD8+ T-cell response did not reveal any immune defects in CXCR3-deficient mice. Yet, when mice were challenged with LCMV intracerebrally, most CXCR3-deficient mice survived the infection, whereas wild-type mice invariably died from CD8+ T-cell-mediated immunopathology. Quantitative analysis of the cellular infiltrate in CSF of infected mice revealed modest, if any, decrease in the number of mononuclear cells recruited to the meninges in the absence of CXCR3. However, immunohistological analysis disclosed a striking impairment of CD8+ T-cells from CXCR3-deficient mice to migrate from the meninges into the outer layers of the brain parenchyma despite similar localization of virus-infected target cells. Reconstitution of CXCR3-deficient mice with wild-type CD8+ T-cells completely restored susceptibility to LCMV-induced meningitis. Thus, taken together, our results strongly point to a critical role for CXCR3 in the positioning of effector T-cells at sites of viral inflammation in the brain.
Christensen
Jeanette Erbo
JE
Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark.
Nansen
Anneline
A
Moos
Torben
T
Lu
Bao
B
Gerard
Craig
C
Christensen
Jan Pravsgaard
JP
Thomsen
Allan Randrup
AR
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D002452:Cell Count; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007157:Immunologic Surveillance / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000472:pathogenicity; D008578:Meninges / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
D015415:Biomarkers; C515188:Cxcr3 protein, mouse; D018960:Hyaluronan Receptors; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine