Abstract
Herpes simplex virus type 2 (HSV-2) is a neurotropic virus that can cause meningitis, an inflammation of the meninges in the central nervous system. T cells are key players in viral clearance, and these cells migrate from peripheral blood into the central nervous system upon infection. Several factors contribute to T cell migration, including the expression of chemokines in the inflamed tissue that attract T cells through their expression of chemokine receptors. Here we investigated CD8+ T cell profile in the spinal cord in a mouse model of herpes simplex virus type 2 neuroinflammation. Mice were infected with HSV-2 and sacrificed when showing signs of neuroinflammation. Cells and/or tissue from spinal cord, spleen, and blood were analyzed for expression of activation markers, chemokine receptors, and chemokines. High numbers of CD8+ T cells were present in the spinal cord following genital HSV-2-infection. CD8+ T cells were highly activated and HSV-2 glycoprotein B -specific effector cells, some of which showed signs of recent degranulation. They also expressed high levels of many chemokine receptors, in particular CCR2, CCR4, CCR5, and CXCR3. Investigating corresponding receptor ligands in spinal cord tissue revealed markedly increased expression of the cognate ligands CCL2, CCL5, CCL8, CCL12, and CXCL10. This study shows that during herpesvirus neuroinflammation anti-viral CD8+ T cells accumulate in the CNS. CD8+ T cells in the CNS also express chemotactic receptors cognate to the chemotactic gradients in the spinal cord. This indicates that anti-viral CD8+ T cells may migrate to infected areas in the spinal cord during herpesvirus neuroinflammation in response to chemotactic gradients.
Highlights
Herpes simplex virus type 2 (HSV-2) is a double-stranded DNA virus that infects through mucosal tissue to establish a latent infection in the central nervous system (CNS) (Kramer, Cook et al 2003; Weller and Coen 2012)
Using a mouse model of HSV-2-induced neuroinflammation, we show that effector CD8+ T cells express a chemokine repertoire that suggests that they have migrated to the CNS
There is a vast increase of CD8+ T cells in the spinal cord during herpes simplex infection, indicating that C D8+ T cells traffic into the CNS during viral neuroinflammation
Summary
Herpes simplex virus type 2 (HSV-2) is a double-stranded DNA virus that infects through mucosal tissue to establish a latent infection in the central nervous system (CNS) (Kramer, Cook et al 2003; Weller and Coen 2012). Accumulated evidence implies that CD8+ T cells are important for the control of acute CNS infection but are necessary for maintenance of HSV latency in infected ganglia (Schiffer and Corey 2013). CXCR3 and its ligand CXCL10 are known to have protective roles in HSV-2 infection as well as to facilitate migration into the CNS (Thapa et al 2008; Thapa and Carr 2009). Chemokines CCL3, CCL5, and CXCL2 have been implicated in enhanced viral clearance and/or survivability (Eo et al 2001; Harle et al 2001; Benencia et al 2003), and in humans chemokines have been characterized in the acute phase of HSV-2 meningitis (Lind et al 2017). The chemokine-receptor profile of CD8+ T cells transmigrating to the CNS in HSV-2 meningitis is not known
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