Sleep restriction reprograms systemic immunity through NK and T cell crosstalk

Insufficient sleep is a recognized risk factor for inflammatory diseases, yet how sleep loss functionally perturbs immune regulation remains unclear. Here, we apply a multi-omics framework combining two-sample Mendelian randomization, sleep-restriction intervention microarray, and PBMC single-cell profiling to dissect immune consequences of sleep loss. Mendelian randomization associated genetically proxied sleeplessness/insomnia symptoms with alterations in 162 plasma proteins and increased risk across 94 clinical diagnosis traits. Gene expression microarray after sleep restriction confirmed immune activation and stress-response programs. Single-cell RNA sequencing revealed PBMC remodeling with increased NK/NKT cells and decreased γδ T cells and dendritic cells, alongside pro-inflammatory pathway activity. Ligand–receptor analysis identified altered intercellular communication patterns, characterized by increasing signals to NK cells and enhancing NK–T cell-associated interfaces. These findings nominate dysregulated NK cell–T cell crosstalk as a putative mechanism underlying sleep-related inflammation and provide prioritized targets for future validation.