Mechanisms of demyelination and axonal damage in a CD8+ T cell-mediated model of spontaneous demyelinating disease

Autoimmune demyelinating diseases of the nervous system are a major cause for neurological impairment in humans. Recent evidence indicates that CD8+ T cells may contribute significantly to pathogenesis in these conditions but the mechanisms by which CD8+ T cells induce damage remain to be established. To understand the mechanisms by which CD8+ T cells may induce nervous tissue injury in vivo, we study an animal model (referred to as L31) that spontaneously develops CD8+ T cell-mediated demyelination and axonal damage in the central nervous system (CNS). In this project, we revealed that CD8+ T cells located in clusters at specific sites within the CNS of L31 mice and their location was associated with areas of demyelination. We showed that oligodendrocytes, but not neurons, from L31 mice up-regulated their expression of major histocompatibility complex class I (MHC I) molecules and had thus the potential to interact with CNS-infiltrating CD8+ T cells in a MHC I-dependent manner before clinical manifestations of disease. We reported that active caspase 3 was present in oligodendrocytes, suggesting that oligodendrocytes undergo apoptosis in L31 mice. We found that CNS-infiltrating CD8+ T cells from L31 mice were activated effector cells and we provided evidence showing that these cells degranulated in situ; nonetheless, we found that demyelination did not occur through either perforin- or Fas/FasL-dependent mechanisms. We also determined the upregulation of the chemokines CCL5 and CXCL9 and the chemokine receptor CXCR3 in the CNS of L31 mice and established that absence of CXCR3 expression was sufficient to inhibit CD8+ T cell accumulation in the CNS, microglial activation, demyelination and disease development in the L31 model, although CXCR3 deficiency did not alter the functional phenotype of transgenic CD8+ T cells. In addition, no compensatory effect for CCR5 could be detected in L31 mice. Finally, we established the presence of CD8+ T cells and tissue damage

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