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).