Publication date: Available online 14 January 2019
Source: Journal of Allergy and Clinical Immunology
Author(s): Luigi Tortola, Helga Pawelski, Sanchaita Sriwal Sonar, Franziska Ampenberger, Michael Kurrer, Manfred Kopf
Abstract
Background
IL-21 is a key player of adaptive immunity with well-established roles in B and cytotoxic T cell responses. IL-21 has been implicated in promotion of effector CD4+ T cells and inhibition of FoxP3+ regulatory T cells (Tregs), 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 homeostasis.
Methods
We used IL-21R-deficient mice to study the impact of IL-21 on T cell responses in models of asthma and colitis. We used mixed bone marrow chimeras and adoptive transfers of naïve CD4+ T cells and Tregs into lymphopenic mice to assess cell intrinsic effects of IL-21. Using various in vitro T cell assays we characterized the mechanism of IL-21-mediated inhibition of Tregs.
Results
We show that IL-21 production by Th2 and Tfh/ex-Tfh cells promotes asthma by inhibiting Tregs. Il21r–/– mice displayed reduced generation of Th2 cells and increased Tregs. In mixed chimeras, we demonstrate that IL-21 promotes Th2 responses indirectly via inhibition of Tregs. Depleting Tregs in Il21r–/– mice restored Th2 generation and eosinophilia. Furthermore, IL-21 inhibited Treg generation in colitic mice. Using competitive transfers of Il21r+/+ and Il21r–/– CD4+ cells, we show that IL-21 directly inhibited expansion of differentiated Tregs, but was dispensable for Th1/Th17 effectors. We show that IL-21 sensitizes Tregs to apoptosis by interfering with the expression of Bcl-2 family genes.
Conclusion
IL-21 directly promotes apoptosis of Tregs and therefore indirectly sustains generation of inflammatory T helper cells and related effector responses.
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