TY - JOUR TI - Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy AU - Cunha, Pedro P AU - Minogue, Eleanor AU - Krause, Lena CM AU - Hess, Rita M AU - Bargiela, David AU - Wadsworth, Brennan J AU - Barbieri, Laura AU - Brombach, Carolin AU - Foskolou, Iosifina P AU - Bogeski, Ivan AU - Velica, Pedro AU - Johnson, Randall S A2 - Siska, Peter A2 - Rathmell, W Kimryn A2 - Böttcher, Martin A2 - Simon-Molas, Helga VL - 12 PY - 2023 DA - 2023/05/11 SP - e84280 C1 - eLife 2023;12:e84280 DO - 10.7554/eLife.84280 UR - https://doi.org/10.7554/eLife.84280 AB - 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. KW - hypoxia KW - immunotherapy KW - lymphocyte subsets KW - cytotoxic T cells KW - CAR-T cell therapy JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -