GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE344nnn/GSE344986/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE344986GEOGSEfalseHuman lung organoid modeling of antiviral tissue-resident T cell responsesTissue-resident immunity comprises a first line of defense against pathogens and enables rapid innate and adaptive memory responses. However, experimental studies have been hindered by a lack of holistic human in vitro models enabling epithelial pathogen infection in the context of tissue-resident immune subsets. In lung, differing notions of transient versus sustained residency of tissue-resident memory T cells (TRM) have questioned the extent to which amnestic recall immunity to respiratory pathogens occurs locally or in concert with secondary lymphoid organs. We thus generated long-term adult human distal lung organoids from intact tissue fragments in 3D air-liquid interface (ALI) culture, which co-preserved epithelial and stromal components with endogenous lung-resident immune cells (T, B, NK, myeloid). The organoid T cells expressed residency and memory markers and preserved T cell receptor (TCR) repertoires of cognate fresh tissue. SARS-CoV-2 vigorously infected the organoid lung epithelium, stimulated inflammatory cytokine production, and crucially, induced SARS-CoV-2-specific, tissue-resident T cell responses. Further, boosting T cells within intact organoids with SARS-CoV-2 peptide pools blunted subsequent SARS-CoV-2 infection, consistent with a component of virus-specific protective TRM function in the absence of secondary lymphoid tissues. Overall, this immunocompetent lung organoid system demonstrates functional control of viral infection by lung-intrinsic memory T cell responses, provides a rationale for local vaccination strategies and validates a novel platform for investigating human tissue-resident immunity in health and disease.2026/09/29GSE344986GSM9989346GSM9989347GSM998934834295344986Homo sapiens