4-1BB Engagement Costimulates NKT Cell Activation and Exacerbates NKT Cell Ligand-Induced Airway Hyperresponsiveness and Inflammation

Multiple studies have demonstrated that 4-1BB (CD137), a member of the TNF receptor superfamily, is expressed on several immune cells including activated T cells. However, the expression and the role of 4-1BB on natural killer T (NKT) cells have not been fully characterized. In this study, it was shown that 4-1BB was not expressed on naive NKT cells but was rapidly induced on activated NKT cells by TCR engagement with α-galactosylceramide (α-GalCer). Also, 4-1BB signaling provided by 3H3, an agonistic anti-4-1BB mAb, promoted NKT cell activation resulting in enhanced cytokine production of NKT cells driven by α-GalCer. When NKT cell-driven airway immune responses were evaluated by intranasal administration of α-GalCer, airway hyperresponsiveness (AHR) and lung inflammation were significantly more aggravated in mice treated with 3H3 and α-GalCer than in mice treated with α-GalCer alone. These aggravations were accompanied by up-regulation of IL-4, IL-13, and IFN-γ production. Interestingly, AHR was not developed in IL-4Rα-deficient mice treated with α-GalCer with or without 3H3 but was exacerbated in IFN-γ-deficient mice. Our study suggests that 4-1BB on NKT cells functions as a costimulatory molecule and exacerbates the induction of NKT cell-mediated AHR, which is dependent on the IL-4Rα-mediated pathway.