Dysregulation of CXCR3 signaling due to CXCL10 deficiency impairs the antiviral response to herpes simplex virus 1 infection.
The chemokine, CXCL10, chemotactic for NK cells, activated T cells, and dendritic cells is highly expressed during viral infections, including HSV-1. The importance of this chemokine to the control of HSV-1 infection was tested using mice deficient in CXCL10 (CXCL10(-/-)). Following corneal infection, HSV-1 viral titers were elevated in the nervous system of CXCL10(-/-) mice, which correlated with defects in leukocyte recruitment including dendritic cells, NK cells, and HSV-1-specific CD8(+) T cells to the brain stem. In the absence of NK cells and HSV-1-specific CD8(+) T cells in wild-type (WT) or CXCL10(-/-) mice, similar levels of virus were recovered in the nervous system, suggesting these cells are responsible for the observed defects in the control of viral replication in CXCL10(-/-) mice. Leukocyte mobilization was also compared between WT, CXCL10(-/-), and mice deficient in the only known receptor for CXCL10, CXCR3 (CXCR3 (-/-)). NK cell mobilization was comparably reduced in both CXCL10(-/-) and CXCR3(-/-) mice relative to WT animals. However, the reduction in mobilization of HSV-1-specific CD8(+) T cells in CXCL10(-/-) was not observed in CXCR3(-/-) mice following HSV-1 infection. The defect was not the result of an alternative receptor for CXCL10, as Ag-specific CD8(+) T cell recruitment was not reduced in mice which were deficient in both CXCL10 and CXCR3. Thus, CXCL10 deficiency results in reduced mobilization of HSV-1-specific CD8(+) T cells as a result of dysregulation of CXCR3 signaling.
Wuest
Todd R
TR
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Carr
Daniel J J
DJ
D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D001933:Brain Stem / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology*; D003316:Corneal Diseases / Q000235:genetics / Q000276:immunology* / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006561:Herpes Simplex / Q000235:genetics / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
D000956:Antigens, Viral; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3