Similar activation-driven transcriptional programs in lung CMV- and flu- specific memory CD8+ T cells despite differences in tissue residency profiles

To investigate whether virus-specific human lung memory CD8⁺ T cells exhibit distinct transcriptional responses based on viral tropism, we stimulated total human lung cells ex vivo with peptide pools from either influenza virus (epithelial-restricted) or cytomegalovirus (CMV, broader tropism). Antigen-specific CD8⁺ T cells were identified using activation-induced markers (CD25 and CD137) and sorted for bulk RNA sequencing. Despite differences in tissue residency phenotypes, influenza- and CMV-specific CD8⁺ T cells displayed highly similar activation-induced transcriptional programs across nine donors, with shared enrichment of inflammatory and T cell signaling pathways. These findings suggest that lung memory CD8⁺ T cells mount comparable responses to antigen stimulation, regardless of viral specificity or residency profile.