IL-21 promotes allergic airway inflammation by driving apoptosis of FoxP3+ regulatory T cells

Background: 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. Objective: We sought to understand the mechanisms by which IL21 controls effector CD4(+) cell responses and Treg cell homeostasis. Methods: 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. Results: We show that IL-21 production by TH2 and follicular helper T/ex-follicular helper T cells promotes asthma by inhibiting Treg cells. Il21r(-/-) mice displayed reduced generation of T(H)2 cells and increased generation of Treg cells. In mixed chimeras we demonstrate that IL-21 promotes T(H)2 responses indirectly through inhibition of Treg cells. Depleting Treg cells in Il21r(-/-) mice restored T(H)2 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(H)1/T(H)17 effectors. We show that IL-21 sensitizes Treg cells to apoptosis by interfering with the expression of Bcl-2 family genes. Conclusion: IL-21 directly promotes apoptosis of Treg cells and therefore indirectly sustains generation of inflammatory TH cells and related effector responses.