Regulatory T cells fail to suppress CD4+ T-bet+ T cells in relapsing multiple sclerosis patients

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and a defect in the regulatory T-cell subset seems to be involved in the pathogenesis of the disease. Foxp3 is a transcription factor that is selectively expressed in CD4(+) CD25(+) regulatory T cells and is required for their development and function. T-bet is a key transcription factor for the development of T helper 1 (Th1) cells. We found that both the percentage of circulating CD4(+) CD25(+) Foxp3(+) cells and Foxp3 expression were lower in relapsing-remitting (RR) MS patients during relapses than during remission. Otherwise, the percentage of CD4(+) T-bet(+) T cells and T-bet expression in CD4(+) T cells were higher in relapsing than in remitting RRMS patients. CD4(+) CD25(+) T cells both from relapsing and from remitting RRMS patients showed significantly less capacity than corresponding cells from healthy subjects to suppress autologous CD4(+) CD25(-) T-cell proliferation, despite a similar Foxp3 expression level. CD4(+) CD25(+) T cells from healthy subjects and patients in remission clearly reduced T-bet mean fluorescence intensity (MFI) in CD4(+) CD25(-) T cells up to a ratio of 1:10, whereas CD4(+) CD25(+) T cells from patients in relapse were able to reduce T-bet expression only at a high ratio. Our data indicate that the increased number of regulatory T (T-reg) cells and the increased Foxp3 expression in circulating CD4(+) CD25(+) T cells may contribute to the maintenance of tolerance in the remission phase of MS. Moreover, the inhibitory capacity of CD4(+) CD25(+) T cells seems to be impaired in relapsing patients under inflammatory conditions, as shown by the high levels of T-bet expression in CD4(+) T cells.