Hypoxia enhances CD8⁺ T_C2 cell-dependent airway hyperresponsiveness and inflammation through hypoxia-inducible factor...

CD8⁺ type 2 cytotoxic T (T_C2) cells undergo transcriptional reprogramming to IL-13 production in the presence of IL-4 to become potent, steroid-insensitive, pathogenic effector cells in asthmatic patients and in mice in a model of experimental asthma. However, no studies have described the effects of hypoxia exposure on T_C2 cell differentiation.

We determined the effects of hypoxia exposure on IL-13-producing CD8⁺ T_C2 cells.

CD8⁺ transgenic OT-1 cells differentiated with IL-2 and IL-4 (T_C2 cells) were exposed to normoxia (21% oxygen) or hypoxia (3% oxygen), and IL-13 production in vitro was monitored. After differentiation under these conditions, cells were adoptively transferred into CD8-deficient mice, and lung allergic responses, including airway hyperresponsiveness to inhaled methacholine, were assessed. The effects of pharmacologic inhibitors of hypoxia-inducible factor (HIF) 1α and HIF-2α were determined, as were responses in HIF-1α-deficient OT-1 cells.

Under hypoxic conditioning, CD8⁺ T_C2 cell differentiation was significantly enhanced, with increased numbers of IL-13⁺ T cells and increased production of IL-13 in vitro. Adoptive transfer of T_C2 cells differentiated under hypoxic conditioning restored lung allergic responses in sensitized and challenged CD8-deficient recipients to a greater degree than seen in recipients of T_C2 cells differentiated under normoxic conditioning. Pharmacologic inhibition of HIF-1α or genetic manipulation to reduce HIF-1α expression reduced the hypoxia-enhanced differentiation of T_C2 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 T_C2 cell differentiation were shown to be mediated through activation of Janus kinase 1/3 and GATA-3.

Hypoxia enhances CD8⁺ T_C2 cell-dependent airway hyperresponsiveness and inflammation through HIF-1α activation. 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 might play a role in the development of steroid-refractory asthma.