Single-cell transcriptomics reveal a hyperacute cytokine and immune checkpoint axis after cardiac arrest in patients with poor neurological outcome

Neurological injury is a major driver for mortality among patients hospitalized after cardiac arrest (CA). The early systemic inflammatory response after CA is associated with neurological injury and mortality but remains poorly defined. We determine the innate immune network induced by clinical CA at single-cell resolution. Immune cell states diverge as early as 6h post-arrest between patients with good or poor neurological outcomes at hospital discharge. Nectin-2+ monocytes and Tim-3+ natural killer (NK) cell subpopulations associate with poor outcomes, and interactome analysis highlight their cross-talk via cytokines and immune checkpoints. Ex vivo studies on peripheral blood cells from CA patients demonstrate that immune checkpoints are a compensatory mechanism for the resolution of inflammation after CA. IFNγ/IL-10 induce Nectin-2 on monocytes; in a negative feedback loop, Nectin-2 suppresses IFNγ production by NK cells. The initial hours after CA may represent a window for therapeutic intervention in the resolution of inflammation via immune checkpoints. PBMC from 12 healthy subjects and 28 post-CA were analyzed and sorted by flow cytometry into Tim-3+ NK cells, Tim-3- NK cells, Nectin-2+ monocytes, and Nectin-2- monocytes. Sorted PBMC were subsequently preparated for RNA sequencing.