FoxP3 Regulates T Follicular Regulatory Cell Function

Abstract

T follicular regulatory (Tfr) cells, a subset of regulatory T (Treg) cells, suppress T follicular helper (Tfh) cell mediated B cell responses. However, it is still unclear how Tfr cells function. In this study, we showed that the transcription factor FoxP3 is an essential regulator of the suppressive function of Tfr cells. By using a FoxP3 knockout model (FoxP3 F/F, UBC ERT2-Cre), we showed that Tfr cells adopt certain Tfh phenotypes and lose their suppression-related molecules when they lose FoxP3. Interestingly, we found that some Tfr cells naturally downregulate FoxP3 in control mice (FoxP3 F/F). This finding inspired us to develop a FoxP3 fate mapper model (Rosa26 lox-stop-lox-Tdtomato, FoxP3-Cre-YFP) which can mark the FoxP3 downregulated Tfr cells with Tdtomato expression. We examined the phenotype of the cells via flow cytometry and assessed the suppressive function of Tfr cells by co-culturing them with B cells and Tfh cells. Our data revealed that Tfr cells that natural downregulate FoxP3 lose the expression of the molecules related to the suppressive function, such as CTLA4, CD25, GITR, ICOS and cannot suppress class switch recombination and antibody production. These findings provide evidence supporting the idea that FoxP3 is critical for Tfr cell suppressive function.