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 (TEff-2), that was only present in critically ill patients and associated with more severe respiratory failure and higher mortality. TEff-2 showed effector activation and inflammatory stress conditioning yet had markedly reduced metabolic transcripts without canonical features of exhaustion. Trajectory analyses positioned TEff-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, TEff-2 represents a latent transcriptional program that delineates a clinically high-risk CD8+ T cell state in critical illness.