Cytotoxic CD8⁺T cell ablation enhances the capacity of regulatory T cells to delay viral elimination in Theiler's murine encephalomyelitis

Abstract

Theiler's murine encephalomyelitis (TME) of susceptible mouse strains is a commonly used infectious animal model for multiple sclerosis. The study aim was to test the hypothesis whether cytotoxic T cell responses account for the limited impact of regulatory T cells on antiviral immunity in TME virus-induced demyelinating disease (TMEV-IDD) resistant C57BL/6 mice. TME virus-infected C57BL/6 mice were treated with (i) interleukin-2/-anti-interleukin-2-antibody-complexes to expand regulatory T cells ("Treg-expansion"), (ii) anti-CD8-antibodies to deplete cytotoxic T cells ("CD8-depletion") or (iii) with a combination of Treg-expansion and CD8-depletion ("combined treatment") prior to infection. Results showed that "combined treatment", but neither sole "Treg-expansion" nor "CD8-depletion," leads to sustained hippocampal infection and virus spread to the spinal cord in C57BL/6 mice. Prolonged infection reduces myelin basic protein expression in the spinal cord together with increased accumulation of β-amyloid precursor protein in axons, characteristic of myelin loss and axonal damage, respectively. Chronic spinal cord infection upon "combined treatment" was also associated with increased T and B cell recruitment, accumulation of CD107b microglia/macrophages and enhanced mRNA expression of interleukin (IL)-1α, IL-10 and tumor necrosis factor α. In conclusion, data revealed that the suppressive capacity of Treg on viral elimination is efficiently boosted by CD8-depletion, which renders C57BL/6 mice susceptible to develop chronic neuroinfection and TMEV-IDD.

Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage

“…However, in TMEV-infected B6 mice, ablation of Foxp3 + Tregs during the acute disease phase of TMEV infection did not accelerate virus clearance (Prajeeth et al, 2014). In contrast, ablation of cytotoxic CD8 + T cells rendered B6 mice susceptible to develop chronic demyelinating neuroinfection comparable to the encephalomyelitis observed in SJL/J mice, which might partly be mediated by boosting the suppressive capacity of Tregs on viral elimination (Ciurkiewicz et al, 2017).…”

“…Inflammatory processes were assessed by histological staining with H&E and additional immunohistochemistry staining with Mac-3 (Bio-Rad ABD Serotec GmbH, Puchheim, Germany), Iba1 (Wako Chemicals GmbH, Neuss, Germany and Abcam, Cambridge, GB), CD3 (DakoCytomation GmbH, Hamburg, Germany), Foxp3 (eBioscience; antibody-clone-FJK-16s-monoclonal/14-5773-80), TMEM119 (Abcam) and Iba1/Mac-3 fluorescent double staining and were analyzed as described recently (Bennett et al, 2016;Bröer et al, 2016;Ciurkiewicz et al, 2017;Waltl et al, 2018). H&E staining of spinal cord was used to examine neuronal necrosis, hypercellularity and perivascular infiltration and scored semi-quantitatively (Gerhauser et al, 2007).…”

Facets of Theiler’s Murine Encephalomyelitis Virus-Induced Diseases: An Update

“…Similarly, neither the adoptive transfer of ex vivo generated T reg nor the expansion of endogenous T reg or the antibody-mediated T reg -depletion sustainably impacts the virus replication in C57BL/6 mice [201,203,206]. Interestingly, the T reg -expansion in CD8-deficient C57BL/6 mice leads to chronic infection and spinal demyelination, demonstrating a modulatory function of T reg on antiviral immunity, overridden by the dominating cytotoxic T cell responses in TMEV-IDD resistant mouse strains [207].…”

TAK1 inhibition in mouse astrocyte cultures ameliorates cytokine‐induced chemokine production and neutrophil migration

“…While the mechanism whereby CNS antigens arrive at peripheral lymphoid organs has been revealed in the last few years, the bidirectional connectivity between the immune system and the brain has been appreciated for the last several decades (Dantzer, O'Connor, Freund, Johnson, & Kelley, 2008). For instance, it is well established that immune cells traffic to the brain during infection, and that adaptive immune responses occurring within the CNS can be beneficial as they serve to rid the tissue of infectious pathogens (Aguilar-Valenzuela et al, 2018;Borrow, Tonks, Welsh, & Nash, 1992;Ciurkiewicz et al, 2018;Welsh, Tonks, Nash, & Blakemore, 1987). However, a substantial amount of evidence also suggests that resident cells of the CNS alter their transcriptional responses and up-regulate cytokine and chemokine expression in response to systemic inflammation brought on by pathogenic infection outside the CNS (Blackmore et al, 2017;Ji, Schachtschneider, Schook, Walker, & Johnson, 2016).…”