High altitude de-acclimatization leads to long-term immune-suppression via upregulating Nrf2 expression in Tregs

Introduction: High-altitude exposure imposes hypoxic, low-pressure, and cold conditions that challenge immune homeostasis. The long-term effects of high-altitude de-acclimatization (HADA) remain poorly understood. Objectives: The purpose of this study is to investigate how HADA affects the immune populations, both quantitatively and functionally, and to dissect the underlying molecular mechanisms involved. Methods: Peripheral blood was collected from both human cohorts and mice models while other immune organs including spleen, thymus and bone marrow were obtained from mice models. Proportions of immune cell populations in peripheral blood and other immune organs were analyzed using flow cytometry. The immune-suppressive functions of Tregs were determined by in vitro co-culture with CD8+ T cells. Transcriptomic and chromatin-accessibility feature induced by HADA were obtained through RNA-seq and ATAC-seq. The functional validation of HADA target gene was performed using specific agonist during in vitro co-culture. Results: HADA perturbed the proportions of immune populations in multiple immune site. Both data from human and mice showed increased regulatory T cells (Tregs) and enhanced immune-suppressive function in the peripheral blood. As a consequence, these Tregs mediated long-term immune suppression, impairing the immunity against tumor cells. Multi-omic analyses predicted Nrf2 as the key mediator of molecular alterations in Tregs caused by HADA, which was further confirmed by the functional assay. Conclusion: High-altitude de-acclimatization mediates the expansion of peripheral Tregs and enhances long-lasting immunosuppressive function of Tregs, increasing the probability of serious health consequences. Nrf2 plays as a key regulator mediating the effects of HADA on Tregs. These findings provide novel insights into altitude-related immune regulation and implications for health management in populations transitioning between high and low altitudes.