CXCR3 Deficiency Increases Susceptibility to Genital Herpes Simplex Virus Type 2 Infection: Uncoupling of CD8+ T-Cell Effector Function but Not Migration
CXCR3 Deficiency Increases Susceptibility to Genital Herpes Simplex Virus Type 2 Infection: Uncoupling of CD8+ T-Cell Effector Function but Not Migration
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DOI：
10.1128/jvi.00854-09
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发表时间：
2009-09-15
影响因子：
5.4
通讯作者：
Carr, Daniel J. J.
中科院分区：
文献类型：
--
作者：
Thapa, Manoj;Carr, Daniel J. J.
CXCR3是一种g蛋白偶联受体，在活化的T细胞、NK细胞和树突状细胞中优先表达。通过γ干扰素调节的趋化因子CXCL9、CXCL10、CXCL11和CXCR3的信号传导在许多病毒病原体的免疫应答中起关键作用。然而，CXCR3与最佳t细胞激活和诱导调节转录因子（即T-bet和eomesodermin）与宿主对生殖器单纯疱疹病毒2型（HSV-2）感染的免疫防御的相关性尚不明确。在这项研究中，我们利用CXCR3（-/-）缺陷小鼠和野生型（WT）对照，评估了生殖器HSV-2感染期间CXCR3表达的需求，评估了小鼠对病毒感染的抗性，重点关注细胞因子/趋化因子反应、募集白细胞的表型分析和CD8(+) T细胞的功能分析。与WT动物相比，CXCR3（-/-）小鼠在感染组织中的病毒负荷以及死亡率升高方面对感染表现出更高的敏感性。CXCR3（-/-）小鼠对病毒感染的不良反应与CD8(+) T细胞通过损害T-bet、穿孔素和颗粒酶B表达而降低细胞毒性T淋巴细胞活性有关。与细胞溶解活性缺陷相对应，检测到CXCR3（-/-）小鼠引流淋巴结中浆细胞样树突状细胞募集减少和CD11c（+）树突状细胞CD80表达减少。总之，这些结果为宿主防御生殖器HSV-2感染所需的CD8(+) T细胞的适当激活提供了CXCR3信号传导的新视角。
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.