IL-21 promotes allergic airway inflammation by driving apoptosis of FoxP3+ regulatory T cells.
- Tortola L Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland. Electronic address: luigi.tortola@biol.ethz.ch.
- Pawelski H Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
- Sonar SS Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
- Ampenberger F Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
- Kurrer M Pathology Institute, Zurich, Switzerland.
- Kopf M Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland. Electronic address: manfred.kopf@ethz.ch.
- 2019-01-18
Published in:
- The Journal of allergy and clinical immunology. - 2019
IL-21
asthma
colitis
mucosal immunity
regulatory T cells
Animals
Apoptosis
Asthma
Colitis
Forkhead Transcription Factors
Interleukin-21 Receptor alpha Subunit
Interleukins
Lung
Mice, Inbred C57BL
Mice, Transgenic
T-Lymphocytes, Regulatory
English
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.
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1016/j.jaci.2018.11.047
- PMID 30654048
- Persistent URL
- https://sonar.ch/global/documents/77833
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