Dimethyl fumarate (DMF; trade name Tecfidera™) is an oral formulation of the fumaric acid ester that is FDA approved for treatment of relapsing-remitting multiple sclerosis (RRMS). To better understand the therapeutic effects of Tecfidera and its rare side-effect of progressive multifocal leukoencephalopathy (PML), we conducted cross-sectional and longitudinal studies by immunophenotyping cells from peripheral blood (particularly T lymphocytes) derived from untreated, 4-6 month and 18-26 month Tecfidera-treated stable RRMS patients using multi-parametric flow cytometry. The absolute numbers of CD4 and CD8 T cells were significantly decreased and the CD4/CD8 ratio was increased with DMF treatment. The proportion of both effector memory (Tem) and central memory T cells (Tcm) were reduced while naïve T cells (Tn) increased in treated patients. T cell activation was reduced with DMF treatment especially among Tem and effector memory RA (Temra) T cells. T helper subsets Th1 (CXCR3+), Th17 (CCR6+), and particularly those expressing both CXCR3 and CD161 were reduced most significantly, while the anti-inflammatory Th2 subset (CCR3+) was increased after DMF treatment. A corresponding increase in IL-4, and decrease in IFNγ and IL-17-expressing CD4+ T cells was observed in DMF-treated patients. DMF in vitro treatment also led to increased T cell apoptosis and decreased activation, proliferation, reactive oxygen species, and CCR7 expression. Our results suggest that DMF acts on specific memory and effector T cell subsets by limiting their survival, proliferation, activation, and cytokine production. Monitoring these subsets could help to evaluate the efficacy and safety of DMF treatment.
Microbial metabolites, produced in the intestine, have significant effects on inflammatory diseases throughout the body. Short-chain fatty acids (SCFAs) have protective effects on experimental autoimmune encephalitis (EAE) responses but the detailed roles of SCFAs and their receptors in regulating autoimmune CNS inflammation have been unclear. SCFAs metabolically regulate T cells and change the phenotype of antigen presenting cells to efficiently induce IL-10
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regulatory T cells. In line with the overall protective effect, blood levels of major SCFAs, such as acetate, propionate and butyrate, are significantly decreased in long-term active progressive multiple sclerosis (MS) patients. Importantly, SCFAs can induce CD4
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effector T cells, which are highly inflammatory when transferred into mice, suggesting that the direct effect of SCFAs on T cells can even be pro-inflammatory in the CNS. In contrast to the moderate protective effect of SCFAs, mice deficient in GPR41 or GPR43 are more resistant to EAE pathogenesis. Thus, despite the overall protective function of SCFAs, SCFAs and their receptors have the potential to regulate autoimmune CNS inflammation both positively and negatively.
Naïve T cells receive stimulation from the positive selecting ligand in the periphery for their survival. This stimulation does not normally lead to overt activation of T cells, as the T cells remain largely quiescent until they receive either antigenic or lymphopenic stimuli. The underlying mechanism responsible for survival and quiescence of the naïve T cells remain largely unknown. Here we report that T cell-specific deletion of Tsc1, a negative regulator of mTOR, resulted in both spontaneous losses of quiescence and cellularity, especially within the CD8 subset. The Tsc1-deficient T cells have increased cell proliferation and apoptosis. Tsc1 deletion affects the survival and quiescence of T cells in the absence of antigenic stimulation. Loss of quiescence but not cellularity was inhibited by rapamycin. Our data demonstrate that TSC-mTOR maintains quiescence and survival of T cells.
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