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

## TL;DR

A gene module called ALARM identifies immune cells in the blood that are ready to move to inflamed tissues and is linked to immune diseases.

## Contribution

The discovery of the ALARM gene module and its role in immune cell recruitment and disease prediction.

## Key findings

- ALARM-expressing cells are reduced in blood but increased in inflamed tissues during rejection and infection.
- The CXCR4–CXCL12 interaction drives T cell migration and metabolic changes.
- ALARM expression is linked to immune-mediated diseases and validated in a pneumonia mouse model.

## Abstract

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.

•ALARM gene module defines circulating immune cells primed for recruitment•ALARM-expressing cells are depleted in blood and enriched in inflamed tissues•CXCR4–CXCL12 axis drives T cell migration, CD69 induction, and glycolytic shift•ALARM predicts immune-mediated diseases across infections and inflammation

ALARM gene module defines circulating immune cells primed for recruitment

ALARM-expressing cells are depleted in blood and enriched in inflamed tissues

CXCR4–CXCL12 axis drives T cell migration, CD69 induction, and glycolytic shift

ALARM predicts immune-mediated diseases across infections and inflammation

Immunology; Rodent immunology; Transcriptomics