Critical illness expands a transcriptionally distinct hypometabolic CD8 ⁺ T effector program associated with respiratory failure and mortality

Immune dysfunction is a major driver of morbidity and mortality in critical illness syndromes including sepsis. Specifically, CD8 ⁺ T cell dysfunction has been linked to organ failure and death. To characterize the immune substructure of circulating CD8 ⁺ T cells in critical illness at high dimension, we used single-cell RNA sequencing of peripheral blood CD8 ⁺ T cells from 38 critically ill patients and 9 healthy controls. We annotated seven CD8 ⁺ T cell clusters, which included a CD8 ⁺ effector subset, termed T effector state 2 (T _Eff-2 ), that was only present in critically ill patients and associated with more severe respiratory failure and higher mortality. T _Eff-2 showed effector activation and inflammatory stress conditioning yet had markedly reduced metabolic transcripts without canonical features of exhaustion. Trajectory analyses positioned T _Eff-2 as a terminal CD8 ⁺ T effector cell fate driven in part by DDIT4 and DUSP1 , which negatively regulate mTOR and MAPK signaling, respectively. Interestingly, this transcriptional program was indistinguishable by classical protein cytometry methods. These results, including the mortality association, were validated in a larger (n=91) independent external cohort of critically ill patients with sepsis. In summary, T _Eff-2 represents a latent transcriptional program that delineates a clinically high-risk CD8 ⁺ T cell state in critical illness.