CD4⁺ T cell flexibility. Naive CD4⁺ T cells interacting with Ag-presenting DCs can acquire expression of Bcl-6. However, their commitment to specific effector lineages is governed by additional signals and the coordinated and antagonistic actions of different transcription factors. Sufficient levels of T-bet or GATA3, or potentially RORγt, will override the repressive effect of Bcl-6 to yield Th1, Th2, or Th17 cells, respectively. Yet some DC-primed naive CD4⁺ T cells will become pre–Tfh cells, defined by CXCR5 and Bcl-6 expression, which differentiate into GC Tfh cells after interactions with cognate B cells. Th1, Th2, and, presumably, Th17 cells retain flexibility in their differentiation programs such that under conditions of sustained Ag (e.g., persistent pathogen infection) they can down-regulate T-bet, Gata3, or RORγt, up-regulate Bcl6, and convert to Tfh cells. Regardless of their origin, Tfh cells drive the differentiation of cognate B cells into memory and plasma cells, which is necessary for long-lived protective Ab responses. The magnitude of Tfh-induced humoral responses is regulated by thymic-derived follicular T reg cells. Although pre–Th1, pre–Th2, pre–Th17, and pre–Tfh cells are illustrated as individual cell types, it is equally possible that Th1, Th2, Th17, and Tfh cells arise from a common CD4⁺ T cell precursor that acquires expression of T-bet, GATA3, RORγt, and Bcl-6, and then differentiates into bona fide effector cells after delivery of appropriate instructive cues. The scheme outlined for Th17 cells differentiating into Tfh cells is speculative. Although Th17 cells shares features with Tfh cells, it is unknown whether this reflects an intrinsic characteristic of Th17 cells or their conversion to Tfh cells.