Regulation of follicular helper T cell subset differentiation in health and disease.

Follicular helper T (TFH) cells play a crucial role in adaptive humoral immunity. They provide help to B cells in the germinal centers (GCs), driving the affinity maturation of antigen-specific antibodies and class switch recombination. TFH cells possess profound heterogeneity in spatial distribution (e.g., GC-TFH, follicular mantle-TFH, circulating TFH, peripheral TFH) and phenotypic characteristics (e.g., TFH1, TFH2, TFH17), which enable TFH cells to respond to diverse immune challenges. This review summarizes the recent progress, including our data, on the TFH regulatory network driven by B-cell lymphoma 6 (Bcl-6) and cellular musculoaponeurotic fibrosarcoma oncogene homolog (c-Maf), and the contradictory roles exhibited by different TFH subsets under disparate pathological conditions such as viral infections, autoimmune diseases, and cancer. Integrating multiple TFH subsets into a systematic framework can provide a new perspective for understanding humoral immune regulation and developing new targeted therapies.