Impact of COVID-19 Severity on Lung Tissue-Resident Memory T Cells

Study of Immune Memory in Post-Infection Lungs

Abstract

Tissue-resident memory T cells, or TRMS, play a significant role in antiviral defense through providing localized immune surveillance in the lung. Unfortunately, their role in COVID-19 is incompletely defined. This study investigated how COVID-19 severity influences TRM cell abundance and transcriptional programs using publicly available single-cell RNA sequencing (scRNA-seq) data from the Human Cell Atlas. After using CellTypist for immune cell annotation and quality control, TRM populations were identified based on canonical markers such as CD69, ITGA1 (CD49a), CXCR6, and ZNF683. Comparative analyses across non-, moderate-, and severe-COVID-19 lung samples revealed that TRM frequency increased with disease severity, with severe cases showing significantly higher TRM proportions than non-COVID controls (p < 0.05). Differential gene expression analysis demonstrated that severe-case TRMs upregulated inflammatory and chemotactic genes, including CCL2, CCL8, CCL3L1, S100A8, S100A9, and S100A12, along with elevated PDCD1 expression indicative of activation and exhaustion. Pathway enrichment analysis further identified increased cytokine–cytokine receptor signaling and metabolic reprogramming pathways among severe TRMs, suggesting an activated yet dysregulated phenotype. These findings suggest that while TRM expansion may contribute to viral clearance, it may also amplify local inflammation during severe disease. This study underscores a severity-dependent remodeling of lung TRM populations during SARS-CoV-2 infection and highlights their potential dual role in protection and pathology. Future studies with larger longitudinal datasets are needed to clarify the causal and functional consequences of these transcriptomic changes.