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<p>Tolerogenic dendritic cells (tolDCs) hold promise for treating autoimmune diseases, potentially restoring antigen-specific immune tolerance without systemic immunosuppression. However, their behavior in vivo remains incompletely understood, particularly in response to microenvironmental factors such as oxygen (O<sub>2</sub>) tension. While tolDCs are typically generated and functionally validated under atmospheric O<sub>2</sub> (21%), physiological O<sub>2</sub> levels (physioxia) in human tissues are considerably lower (3–9%). The primary aim of this study was to assess whether tolDCs manufactured under atmospheric O<sub>2</sub> conditions retain their function under physioxia at 4% O<sub>2</sub>, mimicking tissue environments encountered upon clinical administration. To contextualize these findings, we also evaluated the effect of physioxia during in vitro generation and investigated underlying metabolic adaptations. We demonstrate that tolDCs generated under atmospheric O<sub>2</sub> conditions remain functionally effective in physioxic environments, preserving migratory capacity and the ability to induce T cell hyporesponsiveness. Furthermore, physioxia during tolDC generation impaired monocyte-to-tolDC differentiation efficiency, whereas hallmark tolerogenic features, including low expression of CD80, CD83, and CD86, remained intact. Metabolic profiling revealed a distinct shift under physioxia, with reduced mitochondrial reserve capacity and increased glycolytic activity. This suggests metabolic plasticity without loss of function across O<sub>2</sub> environments. Our findings indicate that physiological O<sub>2</sub> shapes tolDC differentiation and metabolism but does not compromise immunoregulatory traits. Importantly, tolDCs generated under atmospheric O<sub>2</sub> remained functionally competent in physioxic environments, reinforcing their suitability for therapeutic use. By modeling in vivo-relevant O<sub>2</sub> levels, this study provides new insights into how microenvironmental O<sub>2</sub> may shape tolDC behavior following clinical administration.</p>

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Resilience of human tolerogenic dendritic cells to physiological oxygen supports clinical application: functional stability amidst glycolytic and differentiation shifts

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月22日

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  • Antonia Peter,
  • Tamara Traitteur,
  • Sara Calitz,
  • Morgane Vermeulen,
  • Mats Van Delen,
  • Amber Dams,
  • Stefanie Peeters,
  • Carole Faghel,
  • Hans De Reu,
  • Waleed F. A. Marei,
  • Zwi N. Berneman,
  • Nathalie Cools

摘要

Tolerogenic dendritic cells (tolDCs) hold promise for treating autoimmune diseases, potentially restoring antigen-specific immune tolerance without systemic immunosuppression. However, their behavior in vivo remains incompletely understood, particularly in response to microenvironmental factors such as oxygen (O2) tension. While tolDCs are typically generated and functionally validated under atmospheric O2 (21%), physiological O2 levels (physioxia) in human tissues are considerably lower (3–9%). The primary aim of this study was to assess whether tolDCs manufactured under atmospheric O2 conditions retain their function under physioxia at 4% O2, mimicking tissue environments encountered upon clinical administration. To contextualize these findings, we also evaluated the effect of physioxia during in vitro generation and investigated underlying metabolic adaptations. We demonstrate that tolDCs generated under atmospheric O2 conditions remain functionally effective in physioxic environments, preserving migratory capacity and the ability to induce T cell hyporesponsiveness. Furthermore, physioxia during tolDC generation impaired monocyte-to-tolDC differentiation efficiency, whereas hallmark tolerogenic features, including low expression of CD80, CD83, and CD86, remained intact. Metabolic profiling revealed a distinct shift under physioxia, with reduced mitochondrial reserve capacity and increased glycolytic activity. This suggests metabolic plasticity without loss of function across O2 environments. Our findings indicate that physiological O2 shapes tolDC differentiation and metabolism but does not compromise immunoregulatory traits. Importantly, tolDCs generated under atmospheric O2 remained functionally competent in physioxic environments, reinforcing their suitability for therapeutic use. By modeling in vivo-relevant O2 levels, this study provides new insights into how microenvironmental O2 may shape tolDC behavior following clinical administration.