Follicular regulatory T cells (TFR) are a regulatory CD4 (Treg) subset that suppress germinal center (GC) B cell differentiation. Interleukin 21 (IL-21) promotes T follicular helper (TFH) differentiation. In the present study we investigated the modulatory effects of IL-21 on TFR in autoimmune BXD2 mice that develop spontaneous GCs with accumulation of IL-21+TFH cells in the spleen. In BXD2-Il21-/- mice, GL-7+Fas+GC B cells and CXCR5+ICOS+TFHs were significantly reduced, but the frequency of TFR cells was 2-fold higher than that in wild-type BXD2 mice. Most CXCR5+ICOS+CD4 T cells in BXD2-Il21-/- mice highly expressed Treg markers including FoxP3, CTLA4, TGF-β1 and GITR. FoxP3+TFR cells were localized in spleen follicular areas of BXD2-Il21-/- mice. Surprisingly, transfer of TFRs from BXD2-Il21-/- mice into BXD2 mice reduced IgM but not IgG autoantibody producing B cells in the spleen. This may be due to the suppressive effects of IL-21 on TFRs as administration of AdIL-21 increased GC B cells and decreased the ratio of TFR/TFH in the spleen of BXD2-Il21-/- mice in vivo. In vitro, IL-21 increased TFH but decreased TFR cells and significantly reduced Tgfb expression by TFRs. IL-21 also counteracted TFR-induced B cells death and inhibition of TFHs. The present study suggests that IL-21 positively promotes autoreactive GC reactions in BXD2 mice at least partially by decreasing TFRs and compromising the suppressive function of TFRs on B cells and TFHs.
- Copyright © 2013 by The American Association of Immunologists, Inc.