Bystander CD8 T Cell-Mediated Demyelination After Viral Infection of the Central Nervous System

Abstract

Multiple sclerosis, a chronic inflammatory disease of the CNS, is characterized by immune-mediated demyelination. Many patients have a remitting-relapsing course of disease with exacerbations often following unrelated microbial illnesses. The relationship between the two events remains obscure. One possibility is that T cells specific for the inciting microbial pathogen are able to effect demyelination at a site of ongoing inflammation within the CNS. This possibility was examined in mice infected with mouse hepatitis virus, a well-described model of virus-induced demyelination. Using transgenic TCR/recombination activation gene 2−/− mice with only non-mouse hepatitis virus-specific T cells, we show that CD8 T cells are able to cause demyelination in the absence of cognate Ag in the CNS, but only if specifically activated. These findings demonstrate a novel mechanism for immune-mediated neuropathology and show that activated CD8 T cells may serve as important mediators of bystander demyelination during times of infection, including in patients with multiple sclerosis.

Lipopolysaccharide Injection Induces Relapses of Experimental Autoimmune Encephalomyelitis in Nontransgenic Mice via Bystander Activation of Autoreactive CD4+ Cells

“…This scenario is different both from the Ag-dependent adjuvant effects of LPS (60 -63) and from bystander damage which can occur in virally infected mice with a monoclonal T cell repertoire (64 -66). Both the Ag-specific activation of the monoclonal T cells and the simultaneous viral infection at the site of tissue damage are necessary conditions for the induction of bystander damage which can result in diabetes (64), keratitis (65), or encephalitis (66). In sharp contrast, TCR-mediated signals are not required for the LPSinduced bystander activation of Th cells described here.…”

IL-4-Dependent Th2 Collateral Priming to Inhaled Antigens Independent of Toll-Like Receptor 4 and Myeloid Differentiation Factor 88

“…Therefore, chronic Ag-specific Th2 inflammation can potentiate further naive T cell sensitization to distinct allergens in a process we have called collateral priming (Table I). We have used the term collateral priming to describe the process of activation of naive T cells to their cognate Ag by adaptive immune signals to contrast it with the phenomena known as bystander activation (32)(33)(34)(35). Although both processes involve activation of T cells by factors produced by a proximal but distinct T cell population, collateral priming is the activation of a naive T cell to its cognate Ag (as compared with an Ag-nonspecific response).…”

Cutting Edge: Multiple Sclerosis-Like Lesions Induced by Effector CD8 T Cells Recognizing a Sequestered Antigen on Oligodendrocytes

“…Previous studies have shown that CD8 T cells are necessary for the development of a full-blown pathology in animal models of neuroinflammation, but their Ag specificity is still unknown (2,7,8). Similarly, a role for CD8 T cells in demyelination has been clearly illustrated in viral models of CNS inflammation, but the mechanisms involved have remained contentious (9,10). Myelin-specific CD8 T cells can adoptively transfer autoimmune encephalomyelitis but the lesions were reminiscent of ischemic injury with the demyelination associated with more global tissue damage, and few CD8 T cells actually infiltrated the CNS parenchyma (11,12).…”