{"doi":"10.1371/journal.ppat.1009842","title":"Broadly directed SARS-CoV-2-specific CD4+ T cell response includes frequently detected peptide specificities within the membrane and nucleoprotein in patients with acute and resolved COVID-19","abstract":"The aim of this study was to define the breadth and specificity of dominant SARS-CoV-2-specific T cell epitopes using a comprehensive set of 135 overlapping 15-mer peptides covering the SARS-CoV-2 envelope (E), membrane (M) and nucleoprotein (N) in a cohort of 34 individuals with acute (n = 10) and resolved (n = 24) COVID-19. Following short-term virus-specific in vitro cultivation, the single peptide-specific CD4+ T cell response of each patient was screened using enzyme linked immuno spot assay (ELISpot) and confirmed by single-peptide intracellular cytokine staining (ICS) for interferon-γ (IFN-γ) production. 97% (n = 33) of patients elicited one or more N, M or E-specific CD4+ T cell responses and each patient targeted on average 21.7 (range 0-79) peptide specificities. Overall, we identified 10 N, M or E-specific peptides that showed a response frequency of more than 36% and five of them showed high binding affinity to multiple HLA class II binders in subsequent in vitro HLA binding assays. Three peptides elicited CD4+ T cell responses in more than 55% of all patients, namely Mem_P30 (aa146-160), Mem_P36 (aa176-190), both located within the M protein, and Ncl_P18 (aa86-100) located within the N protein. These peptides were further defined in terms of length and HLA restriction. Based on this epitope and restriction data we developed a novel DRB*11 tetramer (Mem_aa145-164) and examined the ex vivo phenotype of SARS-CoV-2-specific CD4+ T cells in one patient. This detailed characterization of single T cell peptide responses demonstrates that SARS-CoV-2 infection universally primes a broad T cell response directed against multiple specificities located within the N, M and E structural protein.","journal":"PLoS Pathogens","year":2021,"id":157275,"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":51,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9653,"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":664294,"name":"Sophia Schulte","orcid":null,"position":1,"is_corresponding":false},{"id":664295,"name":"Matin Kohsar","orcid":null,"position":2,"is_corresponding":false},{"id":663698,"name":"Thomas Theo Brehm","orcid":"0000-0003-1737-161X","position":3,"is_corresponding":false},{"id":663699,"name":"Marissa Herrmann","orcid":"0000-0002-5292-0795","position":4,"is_corresponding":false},{"id":663700,"name":"Hendrik Karsten","orcid":"0000-0002-2767-0405","position":5,"is_corresponding":false},{"id":450497,"name":"Matthias Marget","orcid":null,"position":6,"is_corresponding":false},{"id":663701,"name":"Sven Peine","orcid":"0000-0002-6365-9916","position":7,"is_corresponding":false},{"id":663702,"name":"Alexandra M. Johansson","orcid":"0000-0003-4779-4648","position":8,"is_corresponding":false},{"id":55670,"name":"Alessandro Sette","orcid":"0000-0001-7013-2250","position":9,"is_corresponding":false},{"id":663703,"name":"Marc Lütgehetmann","orcid":"0000-0002-9468-7944","position":10,"is_corresponding":false},{"id":281006,"name":"William W. Kwok","orcid":"0000-0003-4843-4599","position":11,"is_corresponding":false},{"id":55666,"name":"John Sidney","orcid":"0000-0002-0987-405X","position":12,"is_corresponding":false},{"id":449503,"name":"Julian Schulze zur Wiesch","orcid":"0000-0002-5033-1938","position":13,"is_corresponding":false},{"id":90027,"name":"Janna Heide","orcid":"0000-0002-3528-1602","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T23:44:17.471040Z","pmid":"34529740","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":[]}