The debate about the role of CD8+ T cells in chronic neuroinflammation was started by histopathologic studies of active and chronic MS lesions, showing inconsistent results for both numbers and distribution in MS lesions. In some patients' biopsies, large numbers of oligoclonally expanded CD8+ T cells prevailed within active demyelinating lesions (Babbe et al., 2000), while others presented with scarce, often only marginal infiltration of chronic active MS lesions by CD8+ T cells (Traugott et al., 1983b). However, not only the numbers but also the significance of the presence of CD8+ T cells in MS lesions has been heavily debated. On the one hand, there is evidence for a proinflammatory role from different passive transfer EAE models in which cytotoxic, myelin-specific CD8+ T cells initiated severe CNS inflammation IFN-g- and MHC-I dependently (Huseby et al., 2001; Sun et al., 2001). On the other hand, from a histological point of view, CD8+-induced EAE differed significantly from conventional EAE as there were enhanced and prolonged meningeal involvement, extensive neutrophil recruitment, and signs of necrotic cell damage, all of which suggests a somewhat unspecific cytotoxic effect, as seen in other animal models of bystander damage (Banerjee et al., 2004). In sum, the case for CD8+ T cells as the initiating force in chronic neuroinflammation does not seem very strong, but cytotoxic T cells might considerably contribute to axonal and neuronal damage. Furthermore, in Sun's study, absence of CD4+ T cells in RAG-deficient animals delayed disease onset extremely, suggesting an important role
Damage and cell death Protection and repair
Damage and cell death Protection and repair
FIGURE 1.2 The pathogenesis of chronic neuroinflammation. Classically chronic neuroinflammation was regarded as CD4 Thl-mediated autoimmune disease. More recent data rather point to a disregulation of two dichotomous T cell subsets: the highly pathogenic CD4 Th17 cells and the recovery-mediating CD4 Treg. TGF-b, which has been associated with Treg for a long time, also promotes the differentiation of Th17 cells in the context of antigen-specific (re)activation by mature dendritic cells (mDC) secreting the proinflammatory cytokines IL-6 and IL-23. Uninhibited Th17 cells induce a massive recruitment of effector T cells and APC such as macrophages, B cells, and DC to the target organ. The release of proinflammatory cytokines such as IFN-g, TNF-a, and IL-17 promotes CNS inflammation and tissue injury either by directly targeting neurons or indirectly via APC activation, which releases neurotoxic compounds like nitric oxide (NO) and reactive oxygen species (ROS). Further effector mechanisms involved in damage and cell death include perforin-mediated cytotoxicity and CD95 and TRAIL induced oligodendrocyte and neuronal cell death. However, CD95 and TRAIL-mediated apoptosis is also directed against effector lymphocytes, promoting reversal of CNS inflammation. Despite controversial discussions regarding the effector mechanisms of Treg, membrane-bound TGF-b, CTLA-4, and GITR as well as soluble released IL-10 and TGF-b are suggested to be involved in suppression of proinflammatory cells. Additional targets of Treg are DC in which they presumably induce or preserve an immature phenotype (iDC). Some reports also indicate a regulatory role for CD8 T cells via Qa1-mediated mechanisms. Due to dominance of either pathogenic CD4 Th17 or Treg in distinct disease phases, the balance is shifted periodically during the disease course resulting in phases of demyelination and neuronaUxonal degeneration but also phases of remyelination and regeneration.
for endogenous CD4+ T cells in the initiation of clinical disease, which is not the case in a model of CD8+ deficiency (Linker et al., 2005). Interestingly, this study suggested a beneficial role of CD8+ T cells in conventional active EAE. Gold and coworkers describe a severe and mostly lethal EAE in p-2 microglobulin-deficient mice, which lack CD8+ T cells and NK-T cells. They found typical EAE lesions with increased numbers of CD4+ T cells associated with typical but also enhanced macrophage recruitment and equivalent demyelination and axonal damage, and this correlates well with ''classic'' but enhanced, CD4+-affluent EAE pathology. This report supports a regulatory function of CD8+ T cells on CD4+ T cells which might be due to a Qa-1-dependent suppressor effect of CD8+ T cells. Qa-1, a homologue of HLA-E in the human system and considered as atypical MHC, forms heterodimers with p-2 microglobulin, which is favorably expressed by activated CD4+ T cells as well as B cells. Further evidence of a vital role for CD8+ T cell transmitted CD4+ T cell suppression was provided by Cantor and coworkers, who demonstrated elegantly that PLP-induced tolerance in C57Bl/6 could be overcome in Qa-1-deficient mice, while wild-type mice did not develop EAE. If Qa-1 was restituted in the CD4+ T cells by retroviral transfer, those cells regained susceptibility to CD8+-suppression. This mechanism was dependent on CD8+ T cells being present during the CD4+ priming process, and could not be surrogated by nonspecific, activated CD8+ T cells; the specificity of the suppressor CD8+ T cells involved has so far not been revealed (Hu et al., 2004).
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