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Dysregulation of CXCR3 Signaling due to CXCL10 Deficiency Impairs the Antiviral Response to Herpes Simplex Virus 1 Infection¹

Todd R. Wuest^* and Daniel J. J. Carr^2,*,

^* Department of Microbiology and Immunology and Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Principal support for this work is by National Institutes of Health R01 AI067309 (to D.J.J.C.) and a Research to Prevent Blindness Stein Research Professorship (to D.J.J.C.). Additional support includes P20 RR017703 and NEI Core Grant EY12190.

² Address correspondence and reprint requests to Dr. Daniel J. J. Carr, Department of Ophthalmology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Boulevard, Oklahoma City, OK 73104. E-mail address: dan-carr{at}ouhsc.edu

³ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; PI, postinfection; gB, glycoprotein B; TG, trigeminal ganglia; BS, brain stem; DC, dendritic cell; WT, wild type.

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