4.3.3. γδ T cells in MS
Despite limited research, there are some studies that associate γδ T cells with the pathogenesis of MS and EAE. However, their exact role in the process remains uncertain. γδ T cells have been found to accumulate in MS plaques, displaying oligoclonal expansion, which is an indication of their involvement in antigen-specific responses (Blink & Miller, 2009). Like CD8+ T lymphocytes, γδ T cells appear to have a dual role in the pathology. On the one hand, they may have a regulatory effect in EAE, as studies that depleted γδ T cells resulted in a more severe disease and mice lacking γδ T cells exhibited a reduced ability to achieve remission from EAE. On the other hand, studies suggest a pathogenic role for γδ T cells in EAE, as they contribute to a proinflammatory environment and are a primary source of IL-17 and other proinflammatory cytokines in the disease (Komiyama et al., 2006; Lees, Iwakura & Russell, 2008; Ponomarev & Dittel, 2005). Therefore, more research is necessary to determine the circumstances under which γδ T cells may change their role, particularly if these cells are to be explored as a therapeutic target.
4.3.4. CD4 + Regulatory T cells in MS
In TCR transgenic mouse models specific for myelin, CD4+ FOXP3+ Treg cells prevent spontaneous EAE by suppressing CD4+myelin-specific T cell activation in the periphery. MBP-specific T cells acquire an anti-inflammatory phenotype after encountering endogenous antigen presented on lymphoid tissues in the presence of Treg cells (Cabbage, Huseby, Sather, Brabb, Liggitt & Goverman, 2007). However, if Treg cells are absent or immunogenic stimuli are present during the interaction between MBP-specific T cells and peripheral APCs, tolerance is not generated and autoimmunity prevails. The function of Treg cells in preventing inflammation within the CNS is also controversial (McGeachy, Stephens & Anderton, 2005) Although there is a correlation between the presence of IL-10-producing FOXP3+ Treg cells and recovery of the CNS and disease, Treg cells appear to be ineffective in suppressing effector T cells in the CNS until local levels of IL-6 and TNFα decrease. Currently, the mechanisms of suppression, antigen specificity and efficacy of Treg cells in suppressing Th1, Th17 and CD8+ T cells in the CNS are not elucidated. The function of CD4+ Treg cells in the peripheral blood of MS patients appears to be compromised, indicating a weakened ability to restrain the activation of T cells that target myelin in the peripheral compartment. In MS tissue sections, the presence of FOXP3+ Treg cells has not been detected. However, it is unclear whether their absence is a result of a migration defect or reduced survival in the CNS. (Tzartos et al., 2008).
4.3.5. Regulatory CD8 + T cells in MS
The presence of regulatory CD8+ T cells have been observed in both EAE and MS patients. Different subtypes of regulatory CD8+ cells are involved in inhibiting effector CD8+ T cells, including natural CD8+CD122+ T cells, which secrete IL-10 to inhibit effector CD8+ T cells; HLA-G+ CD8+ T cells, which suppress effector T cells through the secretion of soluble factors; induced CD8+ Tregs that act at the CNS level; and CD8+CD28- T cells that can induce tolerogenic effects on dendritic cells and inhibit disease. CD8+ Tregs generated by the expansion of CD4+ effector T cells in the periphery can eliminate activated CD4+ T cells by recognizing the non-classical MHC molecule Qa-1 on their surface. Modulating CD8+ and CD4+ Treg responses may have therapeutic potential for MS patients. MS patients vaccinated with myelin-specific CD4+ T cell clones generate CD8+ Tregs capable of eliminating effector T cells. The benefits of glatiramer acetate therapy, commonly administrated to MS patients, may also be mediated partly by the regulation of CD8+ T cells (Tennakoon, Mehta, Ortega, Bhoj, Racke & Karandikar, 2006).