Autoimmunity or tolerance induction: control of CD8 T cell-mediated immune reactions against CNS oligodencrocytes by local infection

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In the central nervous system, T lymphocytes may exert either protective or harmful effects during immunosurveillance and infections or during autoimmune reactions, respectively. Immune reactions directed against pathogens may also result in permanent damage of brain tissue; thus, the decision is important whether infected cells should be destroyed to save the host organism or not. This project addresses the mechanisms which allow either CD8 T cell (CTL) mediated destruction of oligodendrocytes ((auto)immunity) or, vice versa, induce destruction of the offending CTL (induction of tolerance).We have established a transgenic mouse line, which expresses ovalbumin (OVA) as autoantigen exclusively in the cytoplasm of oligodendrocytes (ODC-OVA mice). Peripheral infection with OVA-expressing Listeria induces an OVA-specific CD8 T cell response characterized by an initial proliferation of CTL and their circulation through the CNS followed by clonal deletion of the autoreactive OVA-specific CD8 T cells in the absence of clinical symptoms and neuropathological alterations. In striking contrast, intracerebral infection with the same pathogen leads to the antigen-specific destruction of OVA-expressing oligodendrocytes, clinically presenting as paretic disorder with persistent neurological symptoms. These observations provide the rationale for our hypothesis that local inflammatory stimuli within the CNS decide whether an intracerebral immune response results in destruction of the antigen-expressing cell or in elimination of the offending CD8 T cell. In this regard, either the direct sensitization of the oligodendrocyte or the indirect activation of microglia may play a role. Thus, this project aims at the identification of the relation between the site of an infection (within or outside the CNS) and a demyelination inducing CTL reaction. Following the detailed characterization of our model the role of several components of the innate and adaptive immune system will be defined. In particularly, we will test the hypothesis whether in this scenario toll-like receptors in the CNS are of pivotal relevance.