Endothelial GARP Governs Longevity of Lung-resident CD8 T cell memory
Tissue-resident memory CD8 T (Trm) cells provide frontline defense against respiratory viral infections, yet their persistence in the lung is remarkably short-lived compared to other barrier sites. The stromal cues that maintain these cells remain poorly defined. Here, we identify lung endothelial cells as a critical niche that sustains antiviral CD8 Trm cells through the activation of TGF-ß. We found that the transmembrane protein GARP, highly expressed on lung endothelial cells, is essential for activating latent TGF-ß and promoting the expression of the tissue-retention molecules CD103 and CD69 on CD8 Trm cells. Endothelial-specific deletion of GARP impaired CD8 Trm maintenance and compromised heterologous immunity against influenza, whereas its overexpression enhanced CD8 Trm populations. Mechanistically, we discovered that influenza-induced TNF triggers persistent, epigenetic repression of the GARP gene in endothelial cells, leading to a loss of TGF-ß signaling and CD8 Trm cell waning. Consequently, neutralization of TNF restored GARP expression and boosted Trm retention. These findings provide a mechanistic basis for the transient nature of lung Trm cells and suggest that modulating the TNF-GARP-TGF-ß axis could be a strategy to achieve durable respiratory immunity. Overall design: scRNA-seq profiling of the lung cells from a 6 weeks old naïve C57BL/6J mouse.