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

T follicular helper (T FH ) cells are CD4 + T cells that facilitate B cell antibody production and B cell memory responses in the germinal centers (GCs) of lymphoid organs. These activities are in turn restrained by T follicular regulatory (T FR ) cells, a population of T cells with unclear origins. Wu et al. now demonstrate that a subpopulation of T FH cells and fibroblastic reticular cells both produce sclerostin domain-containing protein 1 (SOSTDC1), which drives T FR cell generation by inhibiting Wnt–β-catenin signaling. In mice lacking the gene Sostdc1 , T FR cell numbers were substantially decreased and GC responses were enhanced. These insights into T FR cell biology and GC regulation may have important implications for autoantibody-mediated diseases and the future development of vaccines and therapies for autoimmune disease. Science , this issue p. 984 Sclerostin domain-containing protein 1 regulates humoral immunity by promoting the generation of regulatory follicular T cells. 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.