{"doi":"10.1101/2021.03.23.21253885","title":"Expansion of Cytotoxic CD4+ T cells in the lungs in severe COVID-19","abstract":"The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19. IN BRIEF: In severe COVID-19 cytotoxic CD4+ T cells accumulate in draining lymph nodes and in the lungs during the resolving phase of the disease. Re-activated cytotoxic CD4+ T cells and cytotoxic CD8+ T cells are present in roughly equivalent numbers in the lungs at this stage and these cells likely collaborate to eliminate virally infected cells and potentially induce fibrosis. A large fraction of epithelial and endothelial cells in the lung express HLA class II in COVID-19 and there is temporal convergence between CD4+CTL accumulation and apoptosis in the lung. HIGHLIGHTS: In severe COVID-19, activated CD4+ CTLs accumulate in the lungs late in diseaseThese cells likely participate in SARS-CoV-2 clearance, collaborating with CD8+ T cells many of which exhibit an exhausted phenotypeT cells likely contribute to the late exacerbation of inflammationCD4+CTLs have been linked to fibrosis in many disorders and could also be responsible for the eventual induction of fibrosis in a subset of COVID-19 patients. SUMMARY: The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.","journal":"medRxiv","year":2021,"id":214756,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9483,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":108357,"name":"Julie Boucau","orcid":"0000-0001-6731-7238","position":1,"is_corresponding":false},{"id":108356,"name":"Hsiao-Hsuan Kuo","orcid":"0000-0003-3754-3271","position":2,"is_corresponding":false},{"id":282411,"name":"Cory A. Perugino","orcid":"0000-0002-0812-4353","position":3,"is_corresponding":false},{"id":108360,"name":"Vinay S. Mahajan","orcid":"0000-0003-0814-2989","position":4,"is_corresponding":false},{"id":108358,"name":"Jocelyn R. Farmer","orcid":"0000-0003-4901-9848","position":5,"is_corresponding":false},{"id":108379,"name":"Hang Liu","orcid":"0000-0002-7352-7407","position":6,"is_corresponding":false},{"id":108368,"name":"Thomas Diefenbach","orcid":"0000-0002-2798-5909","position":7,"is_corresponding":false},{"id":108361,"name":"Alicja Piechocka‐Trocha","orcid":"0000-0002-1547-524X","position":8,"is_corresponding":false},{"id":108362,"name":"Kristina Lefteri","orcid":null,"position":9,"is_corresponding":false},{"id":108391,"name":"Michael T. Waring","orcid":"0000-0002-6735-5717","position":10,"is_corresponding":false},{"id":809517,"name":"Katherine R. Premo","orcid":null,"position":11,"is_corresponding":false},{"id":108341,"name":"Bruce D. Walker","orcid":"0000-0001-6122-9245","position":12,"is_corresponding":false},{"id":108340,"name":"Jonathan Z. Li","orcid":"0000-0001-9914-9662","position":13,"is_corresponding":false},{"id":234874,"name":"Gaurav D. Gaiha","orcid":"0000-0001-6875-4472","position":14,"is_corresponding":false},{"id":108339,"name":"Xu G. Yu","orcid":"0000-0002-8295-884X","position":15,"is_corresponding":false},{"id":108393,"name":"Mathias Lichterfeld","orcid":"0000-0001-9865-8350","position":16,"is_corresponding":false},{"id":79607,"name":"Robert F. Padera","orcid":"0000-0002-4571-5494","position":17,"is_corresponding":false},{"id":108394,"name":"Shiv Pillai","orcid":"0000-0002-9905-875X","position":18,"is_corresponding":false},{"id":808776,"name":"Naoki Kaneko","orcid":"0000-0002-1349-2660","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-18T23:52:51.201033Z","pmid":"33791730","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":[]}