Metabolic adaptations rewire CD4+ T cells in a subset-specific manner in human critical illness with and without sepsis

Metabolic and immunologic dysfunction, including pathological CD4⁺ T cell immunosuppression, are archetypal in critical illness, but whether these factors are mechanistically linked remains incompletely defined. Here we characterized the metabolic properties of human CD4⁺ T cells from critically ill patients with and without sepsis and healthy adults. CD4⁺ T cells in critical illness showed subset-specific metabolic plasticity, with regulatory T (T_reg) cells preferentially acquiring glycolytic capacity that associated with sustained cellular fitness and worsened clinical illness. Adapted T_reg cells were more metabolically flexible and stabilized suppressive markers FOXP3 and TIGIT under mitochondrial stress. Single-cell transcriptomics suggested reactive oxygen species (ROS) and kynurenine metabolism as drivers of T_reg cell remodeling. Subsequent inhibition of ROS and kynurenine metabolism attenuated glycolytic adaptation and suppressive rewiring, respectively, in T_reg cells. These findings indicate that metabolic dysfunction was a contributor to CD4⁺ T cell remodeling in critical illness and suggest avenues to restore effective immunity.