CD8+ T cells in the central nervous system of mice with herpes simplex infection are highly activated and express high levels of CCR5 and CXCR3

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.

Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19

“…The expansion of cytotoxic CD8+ T cells independently of their specificity is already demonstrated to be an important pathogenic component of gastrointestinal and pulmonary PASC by other groups (Cheon et al, 2021;Phetsouphanh et al, 2022;Su et al, 2022). It has been proven that upregulation of CD8+ T cells contributes to autoimmunity driven demyelination and axonal damage (Bitsch et al, 2000;Friese and Fugger, 2009;Gilmore et al, 2020;Lind et al, 2021), while highly differentiated effector CD8+ T EMRA cells have been associated with neuroinflammation and degeneration (Northfield et al, 2007;Benveniste and Allenbach, 2019). In the frame of SARS-CoV-2 infection independent groups demonstrated that the majority of long-lived antigen specific CD8 memory T cells present TEMRA phenotype (Dan et al, 2021;Jung et al, 2021;Adamo et al, 2022).…”

Essential role of M1 macrophages in blocking cytokine storm and pathology associated with murine HSV-1 infection

“…CCL5 is chemotactic for T cells , eosinophils , and basophils , and is involved in leukocyte recruitment into inflammatory sites [ 88 ]. We also found elevated CCR5 expression in the CNS of HSV-2 infected mice [ 89 ] and severe HSV-1 encephalitis was associated with CCR5 upregulation in the CNS of infected mice [ 90 ].…”

Increased migratory/activated CD8+ T cell and low avidity SARS-CoV-2 reactive cellular response in post-acute COVID-19 syndrome

“…The expansion of cytotoxic CD8+ T cells is already demonstrated from independent groups to be an important pathogenic component of gastrointestinal and pulmonary PASC (18,(33)(34). Regarding the nervous system, it has been proven that upregulation of CD8+ T cells contributes to autoimmunity driven demyelination and axonal damage (35)(36)(37)(38), while highly differentiated effector CD8+ T EMRA cells have been associated with neuroinflammation and degeneration (39)(40). In agreement with our findings of higher frequencies of IFNγ producing CD8+ T cells among PASC, independent groups also detected higher production of TNFα, IFNγ and IL-6, among PASC patients (34,(41)(42)(43).…”

“…EBI2 has been shown to be upregulated in a subtype of ME/CFS (54-56), while in multiple sclerosis it has proven to be functionally expressed with a distinct EBI2 expression to lymphocytes migration correlation pattern, also in the absence of Epstein-Barr virus reactivation (57). In the same line, upregulation of the CXCR3 receptor has been associated with neuronal axonal damage secondary to inflammatory response of T cells a) during or after viral infection (37,58) as well as b) in the frame of autoimmunity (59) mainly in multiple sclerosis patients (36,38).…”