{"doi":"10.1172/jci.insight.184048","title":"NKG2D blockade impairs tissue-resident memory T cell accumulation and reduces chronic lung allograft dysfunction","abstract":"Chronic lung allograft dysfunction (CLAD) substantially limits long-term survival following lung transplantation. To identify potential targets for CLAD prevention, T cells from explanted CLAD lungs and lung-draining lymph nodes, as well as diseased and nondiseased controls were isolated and single-cell RNA sequencing and TCR sequencing were performed. TCR sequencing revealed a clonally expanded population of CD8+ tissue-resident memory T cells (TRMs) with high cytotoxic potential, including upregulation of KLRK1, encoding the co-receptor NKG2D. These cytotoxic CD8+ TRMs accumulated around the CLAD airways and had a 100-fold increase in clonal overlap with lung-draining lymph nodes when compared with non-CLAD lungs. Using a murine model of orthotopic lung transplantation, we confirmed that cytotoxic CD8+ TRM accumulation was due to chronic rejection and not transplantation alone. Furthermore, blocking NKG2D in vivo attenuated the airway remodeling following transplantation and diminished airway accumulation of CD8+ T cells. Our findings support NKG2D as a potential therapeutic target for CLAD, affecting cytotoxic CD8+ TRM accumulation.","journal":"JCI Insight","year":2025,"id":512021,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9615,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":316208,"name":"Madeline A. Lipp","orcid":null,"position":1,"is_corresponding":false},{"id":237172,"name":"Marta Bueno","orcid":"0000-0001-7140-9899","position":2,"is_corresponding":false},{"id":822266,"name":"Andrew Craig","orcid":"0000-0003-3524-2029","position":3,"is_corresponding":false},{"id":730610,"name":"Michelle Rojas","orcid":null,"position":4,"is_corresponding":false},{"id":1370881,"name":"Mohammed Abbas","orcid":"0000-0003-2923-1075","position":5,"is_corresponding":false},{"id":1371422,"name":"Zachary I. Lakkis","orcid":null,"position":6,"is_corresponding":false},{"id":446446,"name":"Byron Chuan","orcid":null,"position":7,"is_corresponding":false},{"id":270566,"name":"John Sembrat","orcid":"0000-0003-4108-803X","position":8,"is_corresponding":false},{"id":642202,"name":"Kentaro Noda","orcid":"0000-0001-8921-1944","position":9,"is_corresponding":false},{"id":352759,"name":"Daniel J. Kass","orcid":"0000-0001-6597-7830","position":10,"is_corresponding":false},{"id":279535,"name":"Kong Chen","orcid":"0000-0001-6980-5454","position":11,"is_corresponding":false},{"id":818388,"name":"Li Fan","orcid":"0000-0002-8764-3687","position":12,"is_corresponding":false},{"id":315201,"name":"Tim D. Oury","orcid":"0000-0002-4253-3214","position":13,"is_corresponding":false},{"id":1350956,"name":"Zihe Zhou","orcid":"0009-0008-6515-5309","position":14,"is_corresponding":false},{"id":879845,"name":"Xingan Wang","orcid":"0000-0002-3718-1883","position":15,"is_corresponding":false},{"id":58178,"name":"John F. McDyer","orcid":"0000-0003-0595-595X","position":16,"is_corresponding":false},{"id":572,"name":"Oliver Eickelberg","orcid":"0000-0001-7170-0360","position":17,"is_corresponding":false},{"id":728223,"name":"Mark E. Snyder","orcid":"0000-0002-0092-9296","position":18,"is_corresponding":false},{"id":356570,"name":"Kaveh Moghbeli","orcid":"0000-0002-9047-5047","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:48:01.269605Z","pmid":"39989456","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}