The cholesterol metabolite 25-hydroxycholesterol restrains the transcriptional regulator SREBP2 and limits intestinal IgA plasma cell differentiation

Diets high in cholesterol alter intestinal immunity. Here, we examined how the cholesterol metabolite 25-hydroxycholesterol (25-HC) impacts the intestinal B cell response. Mice lacking cholesterol 25-hydroxylase (CH25H), the enzyme generating 25-HC, had higher frequencies of immunoglobulin A (IgA)-secreting antigen-specific B cells upon immunization or infection. 25-HC did not affect class-switch recombination but rather restrained plasma cell (PC) differentiation. 25-HC was produced by follicular dendritic cells and increased in response to dietary cholesterol. Mechanistically, 25-HC restricted activation of the sterol-sensing transcription factor SREBP2, thereby regulating B cell cholesterol biosynthesis. Ectopic expression of SREBP2 in germinal center B cells induced rapid PC differentiation, whereas SREBP2 deficiency reduced PC output in vitro and in vivo. High-cholesterol diet impaired, whereas Ch25h deficiency enhanced, the IgA response against Salmonella and the resulting protection from systemic bacterial dissemination. Thus, a 25-HC-SREBP2 axis shapes the humoral response at the intestinal barrier, providing insight into the effect of high dietary cholesterol in intestinal immunity. [Display omitted] •CH25H deficiency enhances Ag-specific IgA plasma cell differentiation in Peyer’s patches•25-HC suppresses SREBP2 transcriptional activity in activated B cells•Srebf2−/− germinal center B cells fail to differentiate into IgA plasma cells•Dietary cholesterol increases 25-HC level and reduces IgA against enteric pathogen 25-hydroxycholesterol (25-HC) is a metabolite of cholesterol generated by the enzyme CH25H. Trindade et al. demonstrate that 25-HC, produced by follicular dendritic cells in response to dietary cholesterol, inhibits the activity of the transcription factor SREBP2 in intestinal germinal center B cells, thereby reducing antigen-specific IgA responses during enteric infection.