IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

Abstract

T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3+ regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.

A distinct subpopulation of CD25−T-follicular regulatory cells localizes in the germinal centers

“…Together with the known importance of IL-2 receptor signaling in the development of KLRG1 + BLIMP-1 hi eTreg cells (17,34), this finding suggests that CD25 − Tfr cells have primarily lost the IL-2-dependent component of eTreg gene expression. We found that ASCL2 may have a role in the down-regulation of CD25; additionally, a recent report has demonstrated that IL-21 signaling in Tregs inhibits CD25 expression via BCL6 (44).…”

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

“…56 The repressor action of IL-21 on Tfr-cell responses was further supported by independent studies. 56 The repressor action of IL-21 on Tfr-cell responses was further supported by independent studies.…”

“…IL-21 (secreted by Tfh cells) inhibits Tfr-cell differentiation through IL-21R/STAT3 signaling, maintaining Tfh and Tfr cells regulated by an IL-21-dependent feedback mechanism. 56 Interestingly, higher CD25 expression levels on IL-21R-deficient Tfr cells led to a heightened signaling in response to IL-2. Therefore, IL-2 consumption is required to promote Tfr-cell development.…”

“…While a balance between Bcl-6 and Blimp-1 is critical for the establishment of a full transcriptional profile of Foxp3 + Tfr cells, store-operated Ca 2+ entry (by ORAI and STIM1 and STIM2) are required for upregulation of the chemokine receptor CXCR5, via NFAT2. [56][57][58][59][60] In IL-21 receptor (IL-21R)-deficient mice, Tfr cells are specifically expanded, following immunization, in a Tfr-cell-intrinsic manner, as IL-21R-deficient T cells preferentially differentiate into Tfr cells. IL-2/STAT5 signaling also inhibits Bcl-6-dependent Tfr-cell program through Blimp-1 upregulation.…”

“…IL-2/STAT5 signaling also inhibits Bcl-6-dependent Tfr-cell program through Blimp-1 upregulation. 56 These authors proposed that IL-21 induces Bcl-6 expression, which in turn limits CD25 expression leading to reduced responsiveness to IL-2. At the same time, Bcl-6 upregulation decreases CD25 (IL-2Rα) expression reinforcing the Tfr-cell program.…”