T follicular regulatory cell differentiation and functional states.

Follicular regulatory T (Tfr) cells enter the B-cell follicle and germinal center, where they control the magnitude, specificity, and duration of the antibody response. However, the temporal and spatial determinants of Tfr differentiation are incompletely understood. Recent advances in fate-mapping, single-cell transcriptomics, and human tissue analyses have revealed that Tfr cells differentiate progressively through distinct differentiation states, a process directed by follicular helper T cells. Tfr differentiation states have unique transcriptional identities, functional roles, and stabilities, revealing intricate feedback loops controlling humoral immunity. Here, we review recent findings on the origins and functions of Tfr cells in mice and humans, how these subsets are intrinsically and extrinsically controlled, and how targeting these pathways may treat human disease.