Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis

Follicular regulatory T cells (T-FR) have been extensively characterized in mice and participate in germinal center responses by regulating the maturation of B cells and production of (auto) antibodies. We report that circulating T-FR are phenotypically distinct from tonsil-derived T-FR in humans. They have a lower expression of follicular markers, and display a memory phenotype and lack of high expression of B cell lymphoma 6 and ICOS. However, the suppressive function, expression of regulatory markers, and FOXP3 methylation status of blood T-FR is comparable with tonsil-derived T-FR. Moreover, we show that circulating T-FR frequencies increase after influenza vaccination and correlate with anti-flu Ab responses, indicating a fully functional population. Multiple sclerosis (MS) was used as a model for autoimmune disease to investigate alterations in circulating T-FR. MS patients had a significantly lower frequency of circulating T-FR compared with healthy control subjects. Furthermore, the circulating T-FR compartment of MS patients displayed an increased proportion of Th17-like T-FR. Finally, T-FR of MS patients had a strongly reduced suppressive function compared with healthy control subjects. We conclude that circulating T-FR are a circulating memory population derived from lymphoid resident T-FR, making them a valid alternative to investigate alterations in germinal center responses in the context of autoimmune diseases, and T-FR impairment is prominent in MS.