Human Foxp3-negative follicular regulatory T cells control IgE responses

specialised T follicular helper (Tfh) cells. A subset of Foxp3+ regulatory T cells (Tregs) has been described in mice, with a prominent role in repressing germinal center reactions that are critical for memory B cell formation and long-lived antibody responses. These specialised Tregs co-opt the Bcl-6-dependent Tfh differentiation pathway in order to access the B cell-rich follicles and have therefore been designated as T follicular regulatory (Tfr) cells. Little is known about the ontogeny or function of human Tfr cells. Here we identify a unique Bcl-6-expressing follicular regulatory T cell in human secondary lymphoid tissue, that lacks Foxp3 expression and the thymic-imprinted Foxp3 methylation pattern, but shares expression of key Treg molecules. These cells, designated Tfr2 cells, are the predominant source of T cell-derived IL-10 in human tonsil. Whereas IL-10 alone promotes B cell terminal differentiation into plasma cells, IL-10-producing Tfr2 cells suppress human B cell differentiation and profoundly limit IgE production. Intriguingly, Tfr2 cells only exert their effects in the presence of Tfr2 cells, at least in part through repressing Tfh-derived IL-21 and CD40L. Tfr2 cells are enriched at human oral-associated lymphoid tissues; continuous exposure to food antigens at these sites make Tfr2 cells an ideal candidate to suppress food allergies.