High-altitude exercise orchestrates a divergent immune landscape: cytotoxic suppression, humoral compensation, and neutrophil functional reprogramming.

The study examined immune adaptations during high-altitude exercise in 46 healthy men using plasma analysis and single-cell sequencing. While low-altitude exercise induced broad immune activation, high-altitude exercise (simulated 5,800 m) suppressed cytotoxic and innate effector programs in CD8 T cells, natural killer cells, monocytes, and dendritic cells. Conversely, humoral immunity was enhanced through activation of plasmablasts and CD4 memory and proliferating T cells. Mature neutrophils were functionally reprogrammed toward phagocytosis and degranulation with expansion of activated circulating neutrophils. A high-altitude-specific program involving chemotaxis and vascular extravasation was identified through plasma and murine muscle transcriptomic analyses. These adaptations were associated with enhanced APRIL, MIF, and Annexin A1 signaling and attenuated CCL-chemokine and complement pathways.