Early commitment of naive human CD4+ T cells to the T follicular helper (TFH) cell lineage is induced by IL-12

T follicular helper (T-FH) cells are a specialized subset of CD4(+) T cells that localize to B-cell follicles, where they are positioned to provide help for the induction of optimal humoral immune responses. Key features of T-FH cells are the expressions of CXCR5, ICOS, interleukin (IL)-21 and BCL-6. The requirements for human T-FH cell development are unknown. Here we show that IL-6, IL-12, IL-21 and IL-23 are capable of inducing IL-21 expression in naive CD4(+) T cells isolated from human tonsils, peripheral blood and cord blood. However, only IL-12 induced sustained expressions of CXCR5 and ICOS on these activated naive CD4(+) T cells, and endowed them with the ability to provide increased help to B cells for their differentiation into immunoglobulin-secreting cells. The effects of IL-12 were independent of interferon-gamma and T-bet, and associated with upregulation of BCL-6 expression. Thus, these cytokines, particularly IL-12, are likely to act at an early stage during dendritic cell-mediated priming of naive CD4(+) T cells into a T-FH cell fate, and thus underpin antibody-mediated immunity. Immunology and Cell Biology (2009) 87, 590-600; doi: 10.1038/icb.2009.64; published online 1 September 2009