SOSTDC1-producing follicular helper T cells promote regulatory follicular T cell differentiation

Germinal center (GC) responses potentiate the generation of follicular regulatory T (T_FR) cells. However, the molecular cues driving T_FR cell formation remain unknown. Here, we show that sclerostin domain-containing protein 1 (SOSTDC1), secreted by a subpopulation of follicular helper T (T_FH) cells and T-B cell border-enriched fibroblastic reticular cells, is developmentally required for T_FR cell generation. Fate tracking and transcriptome assessment in reporter mice establishes SOSTDC1-expressing T_FH cells as a distinct T cell population that develops after SOSTDC1^- T_FH cells and loses the ability to help B cells for antibody production. Notably, Sostdc1 ablation in T_FH cells results in substantially reduced T_FR cell numbers and consequently elevated GC responses. Mechanistically, SOSTDC1 blocks the WNT-β-catenin axis and facilitates T_FR cell differentiation.