Oxygen and immune response (360G-Wellcome-214283_Z_18_Z)

Our goals are centered on understanding how hypoxic response affects immunity. The experiments described are in three key areas: The first of these is myeloid immunosuppression by hypoxia, and the mechanisms of immunosuppression that are regulated by the hypoxia inducible transcription factor (HIF). Here, we will characterize and determine the range of factors produced by M1- and M2-polarized macrophages in HIF1a- and HIF2a-dependent manners by macrophages; we will ask how HIF-driven nitric oxide (NO) homeostasis regulates immunosuppression in hypoxia; and we will determine how HIF-driven myelosuppression acts in a model of acute and chronic viral infection. In the second aim, we will focus on cytotoxic T cell activation by hypoxia and HIF. Here, we will address the role of directed HIF expression on T cell function; and the differential metabolism of T cells as regulated by the VHL- and FIH-mediated control of HIF; including immunometabolic analysis of how those two factors affect T cell function. Our third aim concerns the role of the immunometabolite 2-hydroxyglutarate, and here we will carry out work on enantiomer-specific biology of the metabolites; map chromatin and RNA modifications induced by 2-HG; and investigate the potential use of 2-HG to enhance CAR-T therapies.