Follicular helper T cells progressively differentiate to regulate the germinal center response

Germinal center (GC) B cells undergo affinity selection, dependent upon interactions with CD4(+) follicular helper T (T(FH)) cells. We demonstrate that T(FH) cells progressed through transcriptionally and functionally distinct stages, providing differential signals for GC regulation. They initially localized proximally to mutating B cells, secreted IL-21, induced expression of the transcription factor Bcl-6 and selected high affinity B cell clones. As the GC response evolved, T(FH) cells extinguished IL-21 and switched to IL-4 production, showed robust CD40 ligand expression and promoted the development of antibody-secreting B cells via upregulation of the transcription factor Blimp-1. Thus, T(FH) cells in the B cell follicle progressively differentiated through stages of localization, cytokine production and surface ligand expression to fine-tune of the GC reaction.