Follicular regulatory helper T cells control the response of regulatory B cells to a high-cholesterol diet.

AIMS: B cell functions in the process of atherogenesis have been investigated but several aspects remain to be clarified. METHODS AND RESULTS: In the present study, we show that follicular regulatory helper T cells (TFR) control regulatory B cell (BREG) populations in Apoe-/- mice models on a high-cholesterol diet (HCD). Feeding mice with HCD resulted in upregulation of TFR and BREG cell populations, causing the suppression of proatherogenic follicular helper T cell (TFH) response. TFH cell modulation is correlated with the growth of atherosclerotic plaque size in thoraco-abdominal aortas and aortic root plaques, suggesting that TFR cells are atheroprotective. During adoptive transfer experiments, TFR cells transferred into HCD mice decreased TFH cell populations, atherosclerotic plaque size while BREG cell population and lymphangiogenesis are significantly increased. CONCLUSIONS: Our results demonstrate that, through different strategies, both TFR and TFH cells modulate anti- and pro-atherosclerotic immune processes in an Apoe-/- mice model since TFR cells are able to regulate both TFH and BREG cell populations as well as lymphangiogenesis and lipoprotein metabolism. TRANSLATIONAL PERSPECTIVE: This research demonstrates that TFR cells have atheroprotective functions through modulation of different important biological processes present during atherogenesis. Among these biological processes, lymphangiogenesis and Breg proliferation appear to have particular importance across their ability to modulate immune response, inflammation and cholesterol levels. It may be worth evaluating the use of TFR cells in the primary setting for patients with familial hypercholesterolemia, although TFR cell populations cannot be considered as a means of treating established atherosclerosis.