Corticosteroids enhance CD8⁺ T cell-mediated airway hyperresponsiveness and allergic inflammation by upregulating leukotriene B₄ receptor 1

Background: Leukotriene B₄ (LTB₄) is a potent inflammatory lipid mediator that binds to LTB₄ receptor 1 (BLT1). Ligation of BLT1 by LTB₄ plays an important role in the recruitment of effector memory CD8⁺ T cells into the airways of sensitized and challenged mice. Objectives: The effects of the corticosteroid dexamethasone (DEX) on BLT1-expressing effector memory CD8⁺ T cells and effector memory CD8⁺ T cell-mediated airway hyperresponsiveness (AHR) and allergic inflammation were determined. Methods: Effector memory CD8⁺ T cells were generated from ovalbumin_257-264-primed mononuclear cells from OT-1 mice in the presence of IL-2. In some cultures DEX was added. The effects of DEX on BLT1 expression, LTB₄-induced Ca²⁺ influx, phosphorylation of extracellular signal-regulated kinase 1/2, chemotaxis, and effector memory CD8⁺ T cell-mediated AHR were examined. Results: DEX-treated effector memory CD8⁺ T cells showed significant increases in surface expression of BLT1, LTB₄-induced intracellular Ca²⁺ influx, phosphorylation of extracellular signal-regulated kinase 1/2, and chemotaxis. Upregulation of BLT1 by DEX was accompanied by increased IL-2 receptor expression. Adoptive transfer of DEX-treated effector memory CD8⁺ T cells into ovalbumin-sensitized and ovalbumin-challenged CD8^-/- mice resulted in significant increases in AHR, allergic inflammation, goblet cell metaplasia, and numbers of both CD8⁺ and CD4⁺ T cells in the bronchoalveolar lavage fluid and lungs. Conclusions: Corticosteroids upregulate BLT1 on effector memory CD8⁺ T cells and related signaling pathways and potentiate allergic airway inflammation and AHR induced by these cells.