The elusive identity of T follicular helper cells

Follicular helper T (Tfh) cells provide help to B cells and allow formation of long-lived antibody responses. Despite an improved understanding of the molecular program that drives Tfh cell formation, their definition remains elusive: neither follicular homing ability, Bcl-6 expression nor IL-21 secretion are exclusive properties of T cells that help B cells, and not all follicular T cells are B cell helpers. Indeed some follicular T cells appear to be suppressive. Furthermore, Tfh cells evolve during an immune response and B cells that have recently bound antigen, germinal center (GC) B cells and plasmablasts interact with phenotypically distinct Tfh cells. Here we propose that distinction between non-GC Tfh and GC Tfh cells might reconcile emerging controversies on Tfh cytokine secretion and the requirement of T–B cell interactions and SAP expression for Tfh formation.