Effector Molecules

Cytotoxic T-cell-induced cytotoxicity is mediated predominantly by two independent pathways. The first is a

Figure II Bielschowski staining of spinal cord sections reveals axon preservation in infected class I-deficient mice (P2m-/-) and significant axon loss in infected SJL/J mice. (A) Normal Bielschowski staining in an uninfected SJL/J mouse. (B) Severe loss of axon staining within a demyelinated lesion of an infected SJL/J mouse. (C) Preservation of axon staining in a demyelinated lesion of a chronically infected P2m-- mouse.

Figure II Bielschowski staining of spinal cord sections reveals axon preservation in infected class I-deficient mice (P2m-/-) and significant axon loss in infected SJL/J mice. (A) Normal Bielschowski staining in an uninfected SJL/J mouse. (B) Severe loss of axon staining within a demyelinated lesion of an infected SJL/J mouse. (C) Preservation of axon staining in a demyelinated lesion of a chronically infected P2m-- mouse.

granule-mediated process involving the pore-forming molecule perforin and granzymes. The second is a receptor lig-and interaction that induces apoptosis through Fas (CD95/Apo-1) on the target and Fas ligand (FasL/CD95L/ Apo-lligand) on the effector cell. Both mechanisms are implicated in neurological injury, and both require contact between the target cell and the cytotoxic T-cell. At least one means of such physical contact is the generation of an "immune synapse," formed when the T-cell receptor complex of a cytotoxic T-cell encounters and binds to an MHC class I molecule presenting an appropriate peptide epitope on the surface of a target cell. It was assumed previously that neurons escape immune surveillance through their inability to express MHC class I on the cell surface. However, it has been shown in vivo that during pathological processes, the expression of MHC class I on the surface of neurons is rapidly upregulated. For example, after Theiler's virus infection, MHC class I is rapidly upregulated in most CNS cells, including neurons (Altintas et al., 1993; Lindsley et al., 1991). Therefore, after viral infection, axons and neurons become suitable targets for cytotoxic T-cells that are specific for CD8+-restricted viral epitopes. In addition, soluble

Figure 12 Immunostaining reveals the presence of substantial numbers of CD8+ T-cells within demyelinated lesions of the spinal cord. Green represents anti-CD8 staining; blue shows DAPI-labeled nuclei.

factors such as interferon-a/p (IFN-a/p), released as a result of infection, appear to be involved in the induction of MHC class I on CNS cells (Njenga et al., 1997b). Of interest, electrically silent neurons upregulate MHC class I molecules on their surface (Neumann et al., 1995), thus predisposing them to cytotoxic attack. This suggests that pathological processes such as demyelination that lead to conduction block may cause axons to become particularly vulnerable to cytotoxic T-cell-mediated killing.

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