Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy
- University of Cambridge, United Kingdom
- Georg-August University, Germany
- Karolinska Institute, Sweden
Abstract
Oxygenation levels are a determinative factor in T cell function. Here we describe that the 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 hours 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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided
Article and author information
Author details
Brennan J Wadsworth
Funding
Wellcome Trust (214283/Z/18/Z)
- Randall S Johnson
Knut och Alice Wallenbergs Stiftelse (Scholar)
- Randall S Johnson
Vetenskapsrådet (2019-01485)
- Randall S Johnson
Cancerfonden (CAN2018/808)
- Randall S Johnson
Barncancerfonden (PR2020-007)
- Randall S Johnson
Fundação para a Ciência e a Tecnologia (SFRH/BD/115612/2016)
- Pedro P Cunha
Canadian Institutes of Health Research (Postdoctoral Fellowship)
- Brennan J Wadsworth
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations for ethical experimentation in conformance with Swedish and EU laws and regulations. All of the animals were handled according to approved institutional animal care and use committee protocols. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Ethical Review Board of Northern Stockholm (approval Dnr 19683-2021) and the Swedish Ministry of Agriculture. All surgery was performed under anesthesia, and every effort was made to minimize suffering.
Human subjects: This study was performed in strict accordance with the recommendations for ethical experimentation in conformance with Swedish and EU laws and regulations. All of the animals were handled according to approved institutional animal care and use committee protocols. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Ethical Review Board of Northern Stockholm and the Swedish Ministry of Agriculture. All surgery was performed under anesthesia, and every effort was made to minimize suffering.
Copyright
© 2023, Cunha et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy
eLife 12:e84280.
https://doi.org/10.7554/eLife.84280
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