IL-21 promotes allergic airway inflammation by driving apoptosis of FoxP3+ regulatory T cells - 06/06/19
Abstract |
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 IL-21 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 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.
Conclusion |
IL-21 directly promotes apoptosis of Treg cells and therefore indirectly sustains generation of inflammatory TH cells and related effector responses.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : IL-21, asthma, colitis, regulatory T cells, mucosal immunity
Abbreviations used : BAL, FACS, FoxP3, HDM, ICOS, ILC2, IL-21R, LN, OVA, PD-1, Rag1, ROR, STAT, TFH, Treg, WT
Plan
Research was funded by grants from SNF (SNF 310030B_141175 and SNF 310030_163443/1). |
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Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 143 - N° 6
P. 2178 - juin 2019 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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