The discovery that Bcl-6 was the transcriptional regulator of follicular helper T (Tfh) cells completed the recognition of this population as an effector subset specialized in the provision of help to B cells. Improved reagents and recent models that allow tracking of Bcl-6-expressing T cells have revealed that the decision to become a Tfh cell occurs soon after T cells are primed by dendritic cells and start dividing, before interaction with B cells. The latter are important for sustaining Bcl-6 expression. Bcl-6 coordinates a signaling program that changes expression or function of multiple guidance receptors, leading to Tfh cell localization within germinal centers. This program is not unique to CD4(+) helper T cells; FoxP3(+) regulatory T cells and NKT cells co-opt the follicular differentiation pathway to enter the follicle and become specialized follicular cells. This review will focus on recent insights into the early events that determine Tfh cell differentiation.
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