Sequential Phases of Follicular Helper T Cell Development and Their Impact on Humoral Immune Responses to Vaccination

Abstract Text: Follicular helper T (Tfh) cells play a crucial role in the generation of high-affinity antibodies after vaccination. While the signals triggering Tfh differentiation from naïve T cells have been investigated, those governing subsequent developmental stages leading to optimal effector function remain poorly understood.
We employed fate mapping and reporting strategies for the cytokine IL-21 to elucidate the sequential developmental stages of Tfh differentiation. These stages include a progenitor-like stage (Tfh-Prog), a fully developed effector stage (Tfh-Full), and a post-effector Tfh stage characterized by retention of transcriptional and epigenetic features despite the absence of IL-21 production (Tfh-Ex). We also confirmed sharing of transcriptional features identified in different Tfh stages with human Tfh subsets after vaccination. Notably, Tfh stages are not strictly dictated by anatomical location and have distinct abilities to persist in vivo.
Our findings reveal that the progression through Tfh stages is intrinsically regulated by the transcription factor FoxP1, while extrinsic control is exerted by follicular regulatory T cells. By selectively deleting later Tfh stages (Tfh-Full and Tfh-Ex), we demonstrate that these cells not only mediate germinal center (GC) B cell differentiation and control epitope dominance during early GC responses, but also maintain vaccine-specific B cells in the GC during its contraction, favoring the formation of protective antibodies.
Collectively, these studies elucidate the sequential phases of Tfh development and clarify their role in promoting humoral immunity. Interventions aimed at fine-tuning the progression through Tfh developmental stages could improve humoral responses to vaccination.