Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy.
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.
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Acknowledgements: The authors gratefully acknowledge the flow cytometry facility of the School of the Biological Sciences of the University of Cambridge for their support and assistance in this work. Bioenergetic experiments were performed at the Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK. We acknowledge the Karolinska Institute Small Molecule Mass Spectrometry Core Facility (KI-SMMS), supported by KI/SLL, for support in sample analyses and scientific input. The authors thank Dr. Xiao-Ming Sun and Prof. Marion MacFarlane for providing access to the Seahorse XF96 Bioanalyser and helpful discussions. The authors would particularly like to acknowledge and thank Dr. Cristina M Branco, of Queen’s University, Belfast, for helpful discussions, and for her role in the recruitment of, and facilitation of support for, Pedro P Cunha. The work was funded by the Knut and Alice Wallenberg Scholar Award, the Swedish Medical Research Council (Vetenskapsrådet 2019-01485), the Swedish Cancer Fund (Cancerfonden, CAN2018/808), the Swedish Children’s Cancer Fund (Barncancerfonden PR2020-007), the Portuguese Foundation for Science and Technology scholarship awarded to Pedro P Cunha (SFRH/BD/115612/2016), a Canadian Institutes of Health Research Fellowship to Brennan J Wadsworth and the Principal Research Fellowship (214283/Z/18/Z) to Randall S Johnson from the Wellcome Trust.
Swedish Research Council (2019-01485_VR)