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

FOXP3型 免疫学 细胞毒性T细胞 过继性细胞移植 白细胞介素21 白细胞介素2受体 先天性淋巴细胞 T细胞 生物 细胞生物学 调节性T细胞 过敏性炎症 炎症 获得性免疫系统 免疫系统 体外 生物化学
作者
Luigi Tortola,Helga Pawelski,Sanchaita Sriwal Sonar,Franziska Ampenberger,Michael Kurrer,Manfred Köpf
出处
期刊:The Journal of Allergy and Clinical Immunology [Elsevier]
卷期号:143 (6): 2178-2189.e5 被引量:27
标识
DOI:10.1016/j.jaci.2018.11.047
摘要

BackgroundIL-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.ObjectiveWe sought to understand the mechanisms by which IL-21 controls effector CD4+ cell responses and Treg cell homeostasis.MethodsWe 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.ResultsWe 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 TH2 cells and increased generation of Treg cells. In mixed chimeras we demonstrate that IL-21 promotes TH2 responses indirectly through inhibition of Treg cells. Depleting Treg cells in Il21r−/− mice restored TH2 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 TH1/TH17 effectors. We show that IL-21 sensitizes Treg cells to apoptosis by interfering with the expression of Bcl-2 family genes.ConclusionIL-21 directly promotes apoptosis of Treg cells and therefore indirectly sustains generation of inflammatory TH cells and related effector responses. 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 TH2 and follicular helper T/ex–follicular helper T cells promotes asthma by inhibiting Treg cells. Il21r−/− mice displayed reduced generation of TH2 cells and increased generation of Treg cells. In mixed chimeras we demonstrate that IL-21 promotes TH2 responses indirectly through inhibition of Treg cells. Depleting Treg cells in Il21r−/− mice restored TH2 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 TH1/TH17 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 TH cells and related effector responses.
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