A gene-expression module identifies circulating immune cells with enhanced recruitment to sites of inflammation

Circulating immune cells mediate inflammation through recruitment into tissues, yet how their gene expression programs shape this process remains unclear. Using longitudinal single-cell transcriptomics of peripheral blood from kidney transplant recipients, we identified a conserved gene module termed ALARM, enriched for transcription factors, homing receptors, and early activation markers. ALARM-expressing cells were depleted in blood during rejection but enriched in rejecting grafts and a pig model, consistent with preferential tissue recruitment. Mechanistically, ALARM includes the receptor CXCR4, whose interaction with its ligand CXCL12 drives T cell migration, induces the early activation marker CD69, and triggers a metabolic shift toward glycolysis, as shown in transwell assays. Analysis of public datasets revealed that ALARM is expressed in healthy individuals and downregulated in circulation during infections such as COVID-19 and predictive of multiple immune-mediated diseases, with validation in a pneumonia mouse model. These findings identify ALARM as a central program coordinating immune cell recruitment and effector functions across rejection and infection.