Foxo3 Promotes the Differentiation and Function of Follicular Helper T Cells

Follicular helper T cells (Tfhs) are essential for germinal center (GC) B cell maturation and antibody development. However, the intrinsic mechanisms that regulate Tfh differentiation are largely unknown. Here, we demonstrate that the frequencies of Tfhs and GC B cells, as well as interleukin-21 (IL-21) and anti-ovalbumin (OVA) antibodies, are markedly decreased in forkhead box O3 (Foxo3) knockout mice immunized with OVA. Using mixed bone marrow chimeras and lymphocyte-repopulated Rag1^-/- mice proves that wild-type (WT), but not Foxo3-deficient T cells provoke GC B cell maturation and antibody production. Deficiency of Foxo3 inhibits inducible T cell co-stimulator (ICOS)-induced Tfh differentiation. Chromatin immunoprecipitation assay results suggest that Foxo3 is able to bind to the IL-21 promoter and regulate IL-21 secretion. In conclusion, our study unveils a critical role of Foxo3 in the regulation of Tfh differentiation and IL-21 production. Modulating Foxo3 activity may be beneficial for enhancing or preventing antibody-mediated immune responses.