CXCR3 deficiency increases susceptibility to genital herpes simplex virus type 2 infection: Uncoupling of CD8+ T-cell effector function but not migration.
CXCR3 is a G-protein-coupled receptor preferentially expressed by activated T cells, NK cells, and dendritic cells. Signaling through gamma interferon-regulated chemokines CXCL9, CXCL10, CXCL11, and CXCR3 plays a critical role in the immune response of many viral pathogens. However, the relevance of CXCR3 for optimal T-cell activation and the induction of regulatory transcription factors (i.e., T-bet and eomesodermin) relative to host immune defense against genital herpes simplex virus type 2 (HSV-2) infection have been poorly defined. In this study, we evaluated the requirement of CXCR3 expression during genital HSV-2 infection using mice deficient in CXCR3 (CXCR3(-/-)) along with wild-type (WT) controls, assessing the resistance of mice to viral infection and focusing on the cytokine/chemokine response, phenotypic analysis of recruited leukocytes, and functional analysis of CD8(+) T cells. CXCR3(-/-) mice showed a heightened sensitivity to infection compared to WT animals in terms of the viral burden in infected tissues as well as elevated mortality. The poor response of CXCR3(-/-) mice to viral infection was associated with reduced cytotoxic T-lymphocyte activity through the impairment of T-bet, perforin, and granzyme B expression by CD8(+) T cells. Corresponding with the defective cytolytic activity, a reduction in recruitment of plasmacytoid dendritic cells and CD80 expression in CD11c(+) dendritic cells in the draining lymph nodes of CXCR3(-/-) mice were detected. Collectively, the results provide a new perspective to CXCR3 signaling for the appropriate activation of CD8(+) T cells required for host defense against genital HSV-2 infection.
Thapa
Manoj
M
Department of Microbiology, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA.
Carr
Daniel J J
DJ
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002634:Chemotaxis, Leukocyte; D004198:Disease Susceptibility / Q000276:immunology; D006558:Herpes Genitalis / Q000209:etiology / Q000276:immunology*; D018258:Herpesvirus 2, Human / Q000276:immunology*; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D054367:Receptors, CXCR3 / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology
C515187:CXCR3 protein, human; D054367:Receptors, CXCR3