Follicular regulatory T (Tfr) cells are generated with the responses of germinal center (GC). However, the molecular mechanism on the cell generation is still unknown. Our study found that sclerostin domain-containing protein 1, is essential in the process of Tfr cell generation. With the aid of reporter mice, the results of fate tracking and transcriptome assessment indicated that the Tfh cells expressing SOSTDC1 are identified as a unique T cell population, are developed from SOSTDC1- Tfh cells, and have lost their ability to help B cells in the production of antibodies. It is worth noting that lack of SOSTDC1 results in substantially decreased Tfr cell numbers, and enhanced GC responses. In the aspect of mechanism, SOSTDC1 promotes the differentiation of Tfr cells by blocking Wnt-β-catenin signaling axis