Efficient T-Cell Surveillance of the CNS Requires Expression of the CXC Chemokine Receptor 3

Christensen, Jytte Molin; Nansen, Anneline; Moos, Torben; Liu, Bao; Gérard, Craig; Christensen, Jan Pravsgaard; Thomsen, Allan Randrup

doi:10.1523/jneurosci.0123-04.2004

Cited by 80 publications

(123 citation statements)

References 42 publications

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“…These data support and extend recent studies by Thomsen and colleagues that emphasized different functional roles for chemokine receptors such as CXCR3 and CCR5 in regulating T cell accumulation within the CNS following viral infection [29,30]. Utilizing CXCR3-deficient mice, Christensen et al determined that CXCR3 is not only important for the trafficking of effector CD8 + T cells, but that it plays a role in positioning these cells in the brain during lymphocytic choriomeningitis virus (LCMV) infection [29]. Further studies by de Lemos et al investigated the roles of CXCR3 and CCR5 in CD8 + T cell trafficking to the brain using the LCMV model, and they concluded that a functional overlap between CXCR3 and CCR5 does not exist, since the absence of CCR5 did not further impair CD8 + T cell invasion of the CNS [30].…”

Section: Discussionsupporting

confidence: 91%

“…Although CD8 + and CD4 + T cells expressed similar levels of CXCR3, migration of the CD8 + T cell subset was not dramatically affected, indicating differential roles for CXCR3 in trafficking of T cell subsets. These data support and extend recent studies by Thomsen and colleagues that emphasized different functional roles for chemokine receptors such as CXCR3 and CCR5 in regulating T cell accumulation within the CNS following viral infection [29,30]. Utilizing CXCR3-deficient mice, Christensen et al determined that CXCR3 is not only important for the trafficking of effector CD8 + T cells, but that it plays a role in positioning these cells in the brain during lymphocytic choriomeningitis virus (LCMV) infection [29].…”

Section: Discussionsupporting

confidence: 78%

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Differential roles for CXCR3 in CD4⁺ and CD8⁺ T cell trafficking following viral infection of the CNS

et al. 2006

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Lymphocyte infiltration into the central nervous system (CNS) following viral infection represents an important component of host defense and is required for control of viral replication. However, the mechanisms governing inflammation in response to viral infection of the CNS are not well understood. Following intracranial (i.c.) infection of susceptible mice with mouse hepatitis virus (MHV), mice develop an acute encephalomyelitis followed by a chronic demyelinating disease. The CXC chemokine ligand 10 (CXCL10) is expressed following MHV infection and signals T cells to migrate into the CNS. The functional contribution of the CXCL10 receptor CXCR3 in host defense and disease in response to MHV infection was evaluated. The majority of CD4 + and CD8 + T cells infiltrating the CNS following MHV infection express CXCR3. Administration of anti-CXCR3 antibody reduced CD4 + T cell infiltration (p 0.05), while CD8 + T cell trafficking was not affected. Anti-CXCR3 treatment during chronic disease correlated with improved motor skills and reduced demyelination. The selective effect of anti-CXCR3 treatment on CD4 + T cells was not the result of either reduced proliferation or modulation in chemokine receptor gene expression. Therefore, CXCR3 signaling has a non-redundant role in T cell subset trafficking in response to viral infection.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 78%

Differential roles for CXCR3 in CD4⁺ and CD8⁺ T cell trafficking following viral infection of the CNS

et al. 2006

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“…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).…”

Section: Discussionsupporting

confidence: 90%

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

Zhang

Chan

Liu

et al. 2008

The Journal of Immunology

162

147

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Regional differences in inflammation during viral infections of the CNS suggest viruses differentially induce patterns of chemoattractant expression, depending on their cellular targets. Previous studies have shown that expression of the chemokine CXCL10 by West Nile virus (WNV)-infected neurons is essential for the recruitment of CD8 T cells for the purpose of viral clearance within the CNS. In the current study we used mice deficient for the CXCL10 receptor, CXCR3, to evaluate its role in leukocyte-mediated viral clearance of WNV infection within various CNS compartments. WNV-infected CXCR3-deficient mice exhibited significantly enhanced mortality compared with wild-type controls. Immunologic and virologic analyses revealed that CXCR3 was dispensable for control of viral infection in the periphery and in most CNS compartments but, surprisingly, was required for CD8 T cell-mediated antiviral responses specifically within the cerebellum. WNV-specific, CXCR3-expressing T cells preferentially migrated into the cerebellum, and WNV-infected cerebellar granule cell neurons expressed higher levels of CXCL10 compared with similarly infected cortical neurons. These results indicate that WNV differentially induces CXCL10 within neuronal populations and suggest a novel model for nonredundancy in chemokine-mediated inflammation among CNS compartments.

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“…CXCL9, CXCL10, and CXCL11 lack the Glu-Leu-Arg (ELR) motif common to other members of the CXC chemokine group, and are all inducible by interferon-␥ (IFN-␥) (12,15,27,38). While these chemokines are not detectable in the healthy brain, their expression is highly upregulated following infection of the CNS with various viruses (2,3,10,21,23,24). Deficiency of CXCR3 has been associated with reduced trafficking to and/or positioning of T cells in the CNS in a number of different virally-induced disease models, such as West Nile virus encephalitis (45), mouse hepatitis virus encephalitis (43), and dengue virus encephalitis (18).…”

Section: Ymphocytic Choriomeningitis Virus (Lcmv) Is a Membermentioning

confidence: 99%

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

et al. 2008

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Intracranial infection of mice with lymphocytic choriomeningitis virus (LCMV) results in a lethal neurological disease termed lymphocytic choriomeningitis (LCM) that is mediated by antiviral CD8 ϩ T cells. Previous studies have implicated the chemokine receptor CXCR3 and its ligand CXCL10 in CD8 ϩ T cell trafficking in the brain and in the lethal disease following intracranial infection of mice with the LCMV-Traub strain. Here we investigated the role of CXCR3 in LCM following intracranial infection of mice with the LCMV-Armstrong strain. Significant induction of both CXCL9 and CXCL10 RNA and protein was seen in the central nervous system (CNS) in LCM. Cellular localization of the CXCL9 and CXCL10 RNA transcripts was identified predominantly in infiltrating mononuclear cells, as well as in subpial and paraventricular microglia (CXCL9) and astrocytes (CXCL10). Despite a primary role of interferon (IFN)-␥ in inducing the expression of the CXCL9 gene, and to a lesser extent the CXCL10 gene in LCM, the absence of the IFN-␥ receptor did not influence the disease outcome. This finding suggested that these chemokines may not play a major role in the pathogenesis of LCM. To evaluate this possibility further the development of LCM was examined in mice that were deficient for CXCR3. Surprisingly, in the absence of CXCR3 there was no alteration in mortality, cytokine expression, or T cell infiltration in the CNS, demonstrating that in contrast to LCMV-Traub, CXCR3 is not involved in the pathogenesis of LCMV-Armstrong-induced neurological disease in mice. Our findings indicate that despite similar immunopathogenetic mechanisms involving antiviral CD8 ϩ T cells, whether or not CXCR3 signaling has a role in LCM is dependent upon the infecting strain of LCMV. 425

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Efficient T-Cell Surveillance of the CNS Requires Expression of the CXC Chemokine Receptor 3

Abstract: T-cells play an important role in controlling viral

Cited by 80 publications

References 42 publications

Differential roles for CXCR3 in CD4⁺ and CD8⁺ T cell trafficking following viral infection of the CNS

Differential roles for CXCR3 in CD4⁺ and CD8⁺ T cell trafficking following viral infection of the CNS

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

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

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Efficient T-Cell Surveillance of the CNS Requires Expression of the CXC Chemokine Receptor 3

Abstract: T-cells play an important role in controlling viral

Cited by 80 publications

References 42 publications

Differential roles for CXCR3 in CD4+ and CD8+ T cell trafficking following viral infection of the CNS

Differential roles for CXCR3 in CD4+ and CD8+ T cell trafficking following viral infection of the CNS

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

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

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Product

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Differential roles for CXCR3 in CD4⁺ and CD8⁺ T cell trafficking following viral infection of the CNS

Differential roles for CXCR3 in CD4⁺ and CD8⁺ T cell trafficking following viral infection of the CNS