Increase in natural killer T (NKT) Cell activation in hypoxic environments via the induction of HIF1alpha (162.16)

Abstract

Abstract Tumors often experience hypoxic microenvironments due to poor vascular access in the early stage of neoplastic growth and continue to experience oxygen deficits in late stage progression despite the increase in neovascularization to the primary tumor or metastasis. This persistent hypoxic state selects for tumors cells that are able to compensate for low oxygen levels by increasing use of the glycolytic cycle under aerobic conditions (The Warburg Effect), suppressing apoptosis and inducing decreased genomic stability. These effects have been shown to be mediated, at least in part, by the transcription factor hypoxia inducible factor (HIF)-1alpha. Natural Killer T (NKT) cells are a subset of T cells that recognize a wide range of lipid antigens presented by the MHC Class I-like CD1d molecule. In this study, we sought to investigate the effects of hypoxia induction on CD1d-mediated NKT cell responses. Pharmacological agents were used to induce HIF-1a in LCD1d, and then we assessed their ability to present endogenous antigen to NKT cells. It was found that the induction of HIF-1a resulted in a significant increase in CD1d-mediated NKT cell activation, as assessed by IL-2, GM-CSF, and IL-13 production. The increase in NKT function was not due to with an increase in cell surface expression of CD1d. These results suggest that hypoxia in tumor cells may alter the repertoire of endogenous lipids presented in the context of CD1d which permits their recognition by NKT cells.