Marginal Zone B cells produce 'natural' atheroprotective IgM antibodies in a T-cell-dependent manner

The adaptive immune response plays an important role in atherosclerosis. In response to a high fat/high cholesterol diet, marginal zone B (MZB) cells activate an atheroprotective programme by regulating the differentiation and accumulation of T follicular helper (Tfh) cells. On the other hand, Tfh cells activate the germinal centre response, which promotes atherosclerosis in part through the production of class-switched high-affinity antibodies. However, the direct role of Tfh cells in atherosclerosis remains poorly understood. Here, using a low-density lipoprotein receptor deficient (Ldlr-/-) atherogenic mouse model with selective genetic deletion of Tfh cells, we unexpectedly found that Tfh protect from early atherosclerosis. Mice lacking Tfh had decreased class-switched IgG antibodies against oxidation-specific epitopes (OSE), but also decreased atheroprotective natural IgM-type anti-phosphorycholine (PC) antibodies, despite no alteration of natural B1 cells. RNAseq of MZB cells showed that these cells failed to activate their antibody-secreting machinery in the absence of Tfh. Moreover, MZB cell deficiency in Ldlr-/- mice was associated with a significant decrease in atheroprotective IgM antibodies, including natural anti-PC IgM. In humans, we find a positive correlation between circulating MZB-like cells and anti-OSE IgM antibodies. Finally, we identify an important role for IL18 signalling in high fat/high cholesterol diet-induced Tfh. Our findings reveal a previously unsuspected role of MZB cells in regulating atheroprotective “natural” IgM antibody production in a Tfh-dependent manner, which could have important pathophysiological and therapeutic implications.