CD8-deficient SJL mice display enhanced susceptibility to Theiler's virus infection and increased demyelinating pathology

Abstract

Theiler's murine encephalomyelitis virus (TMEV) infection of the central nervous system (CNS) induces a chronic, progressive demyelinating disease in susceptible mouse strains characterized by inflammatory mononuclear infiltrates and spastic hind limb paralysis. Our lab has previously demonstrated a critical role for TMEV- and myelin-specific CD4(+) T cells in initiating and perpetuating this pathology. It has however, also been shown that the MHC class I loci are associated with susceptibility/resistance to TMEV infection and persistence. For this reason, we investigated the contribution of CD8(+) T cells to the TMEV-induced demyelinating pathology in the highly susceptible SJL/J mouse strain. Here we show that beta2M-deficient SJL mice have similar disease incidence rates to wild-type controls, however beta2M-deficient mice demonstrated earlier onset of clinical disease, elevated in vitro responses to TMEV and myelin proteolipid (PLP) epitopes, and significantly higher levels of CNS demyelination and macrophage infiltration at 50 days post-infection. beta2M-deficient mice also displayed a significant elevation in persisting viral titers, as well as an increase in macrophage-derived pro-inflammatory cytokine mRNA expression in the spinal cord at this same time point. Taken together, these results indicate that CD8(+) T cells are not required for clinical or histologic disease initiation or progression in TMEV-infected SJL mice. Rather, these data stress the critical role of CD4(+) T cells in this capacity and further emphasize the potential for CD8(+) T cells to contribute to protection from TMEV-induced demyelination.

CD8+ T Cells Cause Disability and Axon Loss in a Mouse Model of Multiple Sclerosis

“…We also acknowledge that the role of CD8 + T cells in axon injury may be complicated or reversed in some animal models of demyelinating disease [30]. However, our current findings provoke a cautious optimism that manipulation of CD8 + T cells may be therapeutically relevant to human MS.…”

Chronic social stress impairs virus specific adaptive immunity during acute Theiler's virus infection

“…Borrow et al (1992) reported a higher acute phase viral load as well as accelerated onset and increased severity for the chronic phase following selective depletion of CD8+ T cells prior to infection. Further supporting a role for CD8+ T lymphocytes, both β-2 microglobulin deficient (Begolka et al, 2001; Fiette et al, 1993; Miller et al, 1995; Pullen et al, 1993) and perforin-deficient (Palma et al, 2001; Murray et al, 1998; Rossi et al, 1998) mice are rendered susceptible to chronic demyelination, presumably due to a disruption of antigen presentation and altered CD8 + T cell effector function leading to impaired viral clearance.…”

Immune response in peripheral axons delays disease progression in SOD1G93A mice

“…This scenario resembles that previously reported in experimental mouse models of axon remyelination in which the proliferation and differentiation of oligodendrocytes precursor cells were accompanied by immune cells infiltration [ 52 – 54 ]. Notably, the depletion or pharmacological inhibition of macrophages following toxin- or virus-induced demyelination leads to an impairment of remyelination [ 55 – 57 ], as does an absence of T cells [ 58 , 59 ]. This evidence suggests that protective autoimmunity is a physiologically evoked mechanism through which the body harnesses the immune system in order to protect itself against neuronal degeneration.…”