Hypoxia Enhances CD8+ Tc2 Dependent Airway Hyperresponsiveness and Inflammation Through Hypoxia Inducible Factor 1α

Publication date: Available online 17 January 2019

Source: Journal of Allergy and Clinical Immunology

Author(s): Fangkun Ning, Katsuyuki Takeda, Michaela Schedel, Joanne Domenico, Anthony Joetham, Erwin W. Gelfand

Abstract

Background

CD8+ T cells (Tc2) become potent, steroid-insensitive pathogenic effector cells in experimental asthma undergoing transcriptional reprogramming to IL-13 production in the presence of IL-4. However, no studies have described the effects of hypoxia exposure on Tc2 differentiation.

Objective

We determined the effects of hypoxia exposure on IL-13-producing CD8+ Tc2 cells.

Methods

CD8+ transgenic OT1 cells, differentiated with IL-2 and IL-4 (Tc2 cells) were exposed to normoxia (21% O₂) or hypoxia (3% O₂) and IL-13 production in vitro was monitored. Following differentiation under these conditions, cells were adoptively transferred into CD8-deficient mice and lung allergic responses including airway hyperesponsiveness to inhaled methacholine were assessed. The effects of pharmacologic inhibitors of hypoxia inducible factor 1α (HIF-1α) and HIF-2α were determined as were responses in HIF-1α-deficient OT1 cells.

Results

Under hypoxic conditioning, CD8+ Tc2 differentiation was significantly enhanced with increased numbers of IL-13+ T cells and increased production of IL-13 in vitro. Adoptive transfer of Tc2 cells differentiated under hypoxia restored lung allergic responses in sensitized and challenged CD8-deficient recipients to a greater degree than seen in recipients of Tc2 cells differentiated under normoxia. Pharmacologic inhibition of HIF-1α or genetic manipulation to reduce HIF-1α expression reduced the hypoxia-enhanced differentiation of Tc2 cells, IL-13 production, and the capacity of transferred cells to restore lung allergic responses in vivo. IL-4-dependent, hypoxia-mediated increases in HIF-1α and Tc2 differentiation were shown to be mediated through activation of JAK1/3 kinase and GATA3.

Conclusions

Hypoxia enhances CD8+ Tc2-dependent airway hyperresponsiveness and inflammation through activation of HIF-1α. These findings coupled with the known insensitivity of CD8+ T cells to corticosteroids suggests that activation of the IL-4-HIF-1α-IL-13 axis may play a role in the development of steroid-refractory asthma.

Graphical abstract

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