role of th1 and th17 cd4+ t cell subsets in the pathogenesis of ...

studies between MS susceptibility and the MHC class II region. The development of
“humanized mice”, in which the animals express transgenes derived from MS patients,
has helped better understanding of the effects of individual genetic variations on
disease development. For example, mice engineered to express both the HLA‐
DRB1*1501 allele and a human TCR that recognizes MBP peptide 85‐99 in the context
of HLA‐DR2b were found to spontaneously develop MS‐like disease (Madsen et al.,
1999).
The importance of CD4 + helper T cells in EAE is the main topic of this thesis and will be
addressed in more detail in further sections.
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1.3.2 CD4 + REGULATORY T CELLS
Regulatory CD4 + T cells (Tregs) were described for the first time some years ago and
were defined as an independent T cell population, derived from a naïve precursor and
capable of suppressing the function of other T cells. These cells express the CD25
marker, the alpha chain of the IL‐2 receptor as found later, and their development and
function is dependent on the transcription factor forkhead box P3 (Foxp3). Foxp3 + Tregs
derived from the thymus are denominated as naturally occurring Tregs (nTregs).
Alternatively, they can be differentiated from naïve CD4 + T cell precursors, the induced
Tregs (iTregs). These cells produce high amounts of TGFβ, an anti‐inflammatory
cytokine. Mice mutant in Foxp3, termed scurfy mice, develop lethal autoimmune
syndrome, resultant from deficiency of CD4+CD25+ regulatory T cells (Fontenot et al.,
2003). Foxp3 + Tregs have been shown to play a role in the resolution of inflammatory
immune responses, and therefore have been suggested as targets of a potential
therapeutic target in the treatment of CNS autoimmune disease (Stephens et al., 2009).
Indeed, depletion of CD4 + CD25 + Tregs inhibited EAE recovery and adoptive transfer of
these cells provided protection (McGeachy et al., 2005). However, the mechanisms of
action of Tregs in autoimmunity are not well understood and there are EAE studies
reporting the failure of Tregs to control the auto‐antigenic inflammatory responses,
which can doubts of the possible inefficacy of treating autoimmune diseases with Tregs
(Korn et al., 2007b). One possible explanation might be the close relationship between