Follicular regulatory T (Tfr) cells act as the regulatory counterpart of follicular helper T (Tfh) cells to suppress germinal center (GC) B cell differentiation. We recently showed that interleukin‐21 (IL‐21) promoted Tfh cell differentiation in autoimmune BXD2 mice that develop spontaneous GCs. This study was undertaken to determine the modulatory effects of IL‐21 on Tfr cells and the Tfr cell to Tfh cell balance in BXD2 mice.

The percentage and phenotype of Tfr cells were determined in BXD2 and BXD2‐IL21^−/− mice. The effects of IL‐21 on Tfr cells and the Tfr cell:Tfh cell ratio were evaluated. Sorted Tfr cells from BXD2‐IL21^−/− mice were cocultured with Tfh cells and B cells, or transferred into BXD2 mice to determine their function.

The percentages and numbers of GC B cells and Tfh cells were significantly reduced, but the percentage of Tfr cells was 2‐fold higher in BXD2‐IL21^−/− mice than in wild‐type BXD2 mice. Administration of AdIL‐21 to BXD2‐IL21^−/− mice decreased the percentages and numbers of Tfr cells and the Tfr cell:Tfh cell ratio but increased the number of GC B cells in the spleen. Recombinant murine IL‐21 suppressed FoxP3 and significantly reduced Tgfb1, Il2, and Gitr but enhanced Il21, Il6, Pd1, Cxcr5, and Icos expression in Tfr cells. IL‐21 also counteracted Tfr cell–mediated inhibition of antibody secretion in the Tfh cell–B cell coculture system. Transfer of Tfr cells into young BXD2 mice reduced GC size and decreased the numbers of autoantibody‐producing B cells.

Our findings indicate that high levels of IL‐21 selectively enhance Tfh cell differentiation but inhibit Tfr cell commitment and the suppressive function of Tfr cells on Tfh cells and B cells, suggesting that IL‐21 skews the balance from Tfr cells to Tfh cells to promote autoreactive GC reactions in BXD2 mice.