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.
IFN-gamma-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.
Christensen
Jeanette Erbo
JE
Institute of Medical Microbiology and Immunology, University of Copenhagen, Denmark.
de Lemos
Carina
C
Moos
Torben
T
Christensen
Jan Pravsgaard
JP
Thomsen
Allan Randrup
AR
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D007157:Immunologic Surveillance / Q000276:immunology*; D007700:Kinetics; D008024:Ligands; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008587:Meningitis, Viral / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000276:immunology / Q000378:metabolism*
D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; C515203:Cxcl11 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D008024:Ligands; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine