CXCL10 Is the Key Ligand for CXCR3 on CD8+ Effector T Cells Involved in Immune Surveillance of the Lymphocytic Choriomeningitis Virus-Infected Central Nervous System

Abstract

IFN-γ-inducible protein 10/CXCL10 is a chemokine associated with type 1 T cell responses, regulating the migration of activated T cells through binding to the CXCR3 receptor. Expression of both CXCL10 and CXCR3 are observed during immunopathological diseases of the CNS, and this receptor/ligand pair is thought to play a central role in regulating T cell-mediated inflammation in this organ site. In this report, we investigated the role of CXCL10 in regulating CD8+ T cell-mediated inflammation in the virus-infected brain. This was done through analysis of CXCL10-deficient mice infected intracerebrally with lymphocytic choriomeningitis virus, which in normal immunocompetent mice induces a fatal CD8+ T cell-mediated meningoencephalitis. We found that a normal antiviral CD8+ T cell response was generated in CXCL10-deficient mice, and that lack of CXCL10 had no influence on the accumulation of mononuclear cells in the cerebrospinal fluid. However, analysis of the susceptibility of CXCL10-deficient mice to lymphocytic choriomeningitis virus-induced meningitis revealed that these mice just like CXCR3-deficient mice were partially resistant to this disease, whereas wild-type mice invariably died. Furthermore, despite marked up-regulation of the two remaining CXCR3 ligands: CXCL9 and 11, we found a reduced accumulation of CD8+ T cells in the brain parenchyma around the time point when wild-type mice succumb as a result of CD8+ T cell-mediated inflammation. Thus, taken together these results indicate a central role for CXCL10 in regulating the accumulation of effector T cells at sites of CNS inflammation, with no apparent compensatory effect of other CXCR3 ligands.

CXCR3 Mediates Region-Specific Antiviral T Cell Trafficking within the Central Nervous System during West Nile Virus Encephalitis

“…NT_109320, NW_001030791, NT_039339), our analyses would indicate that CXCL10 is the relevant CXCR3 ligand expressed in the CNS during WNV encephalitis in these animals. These results agree with recent studies examining intracranial inoculation with lymphocytic choriomeningtis virus (LCMV) or dengue virus in which both CXCL10 and CXCR3 were determined to be required for the migration of virus-specific, effector T cells into LCMVinfected meninges and into dengue-infected brains (57)(58)(59). Additionally, nonredundant roles for these two chemokines were recently demonstrated in a model of HSV-1 corneal infection in which CXCL9 alone was required for CD4 T cell infiltration into this tissue site (60).…”

“…Increased viral loads were observed during CNS infection of CXCL10 Ϫ/Ϫ and CXCR3 Ϫ/Ϫ mice with HSV-1, MHV, and LCMV but not during infections with influenza A or murine cytomegalovirus (26,58,60,61). We observed increased viral loads specifically within the cerebella of CXCR3 Ϫ/Ϫ , WNVinfected mice, which correlated with the increased proportions of WNV-specific, CXCR3-expressing T cells that traffic to this site during WNV encephalitis.…”

Unaltered Neurological Disease and Mortality in CXCR3-Deficient Mice Infected Intracranially with Lymphocytic Choriomeningitis Virus-Armstrong

“…Following IC LCMV infection in mice, CXCL10 RNA levels are induced in the CNS prior to leukocyte recruitment (2,3,9). Furthermore, CXCR3-deficient mice (10) and CXCL10-deficient mice (9) were reported to be partially protected from lethal LCM, and increased survival in these mice was paralleled by reduced infiltration of the CNS parenchyma by T cells, and reduced levels of IFN-␥ in the CNS (10).…”

Distinct neural stem cell tropism, early immune activation, and choroid plexus pathology following coxsackievirus infection in the neonatal central nervous system

“…The substantial induction of MHC class I gene expression by LCMV may account for the high numbers of cytotoxic T lymphocytes typically observed following LCMV infection. 28,49 In GFP-CVB3-infected mice, MHC class I gene expression was either absent or observed at very low levels. These results parallel previous findings suggesting the potent ability of CVB3 to decrease MHC class I gene expression by shutting down host cell translation and inhibiting surface expression of these key immune activation molecules.…”

“…15 Similarly, while the cellular targets of infection and the subsequent immune response have been extensively studied for LCMV, the virus remains a significant prenatal and postnatal threat and few effective treatments exist. 16,25,28,29 We hypothesize that a direct comparison of these two viruses during early infection of the neonatal CNS may help determine previously unidentified targets of infection, illuminate the neonatal host immune response following early infection, and clarify the mechanism of viral pathogenesis. The brains of 1-day-old CVB3 and LCMVinfected mice were analyzed for gene expression changes at 12,24, and 48 h post infection (PI) utilizing Illumina BeadArray Technology (MouseWG-6 v2 Expression Beadchips) in order to reveal the global neonatal host response for both neurotropic viral infections.…”