IL-21 is a key player of adaptive immunity, with well-established roles in B-cell and cytotoxic T-cell responses. IL-21 has been implicated in promotion of effector CD4⁺ T cells and inhibition of forkhead box P3–positive regulatory T (Treg) cells, but the mechanism and functional relevance of these findings remain controversial.

We sought to understand the mechanisms by which IL-21 controls effector CD4⁺ cell responses and Treg cell homeostasis.

We used IL-21 receptor–deficient mice to study the effect of IL-21 on T-cell responses in models of asthma and colitis. We used mixed bone marrow chimeras and adoptive transfer of naive CD4⁺ T cells and Treg cells into lymphopenic mice to assess the cell-intrinsic effects of IL-21. Using various in vitro T-cell assays, we characterized the mechanism of IL-21–mediated inhibition of Treg cells.

We show that IL-21 production by T_H2 and follicular helper T/ex–follicular helper T cells promotes asthma by inhibiting Treg cells. Il21r^−/− mice displayed reduced generation of T_H2 cells and increased generation of Treg cells. In mixed chimeras we demonstrate that IL-21 promotes T_H2 responses indirectly through inhibition of Treg cells. Depleting Treg cells in Il21r^−/− mice restored T_H2 generation and eosinophilia. Furthermore, IL-21 inhibited Treg cell generation in mice with colitis. Using competitive transfer of Il21r^+/+ and Il21r^−/− CD4⁺ cells, we show that IL-21 directly inhibited expansion of differentiated Treg cells but was dispensable for T_H1/T_H17 effectors. We show that IL-21 sensitizes Treg cells to apoptosis by interfering with the expression of Bcl-2 family genes.

IL-21 directly promotes apoptosis of Treg cells and therefore indirectly sustains generation of inflammatory T_H cells and related effector responses.