Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom; Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
David Bargiela
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
Laura Barbieri
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom; Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
Carolin Brombach
Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
Iosifina P Foskolou
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom; Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
Oxygenation levels are a determinative factor in T cell function. Here, we describe how oxygen tensions sensed by mouse and human T cells at the moment of activation act to persistently modulate both differentiation and function. We found that in a protocol of CAR-T cell generation, 24 hr of low oxygen levels during initial CD8+ T cell priming is sufficient to enhance antitumour cytotoxicity in a preclinical model. This is the case even when CAR-T cells are subsequently cultured under high oxygen tensions prior to adoptive transfer. Increased hypoxia-inducible transcription factor (HIF) expression was able to alter T cell fate in a similar manner to exposure to low oxygen tensions; however, only a controlled or temporary increase in HIF signalling was able to consistently improve cytotoxic function of T cells. These data show that oxygenation levels during and immediately after T cell activation play an essential role in regulating T cell function.
