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Following short-term virus-specific <jats:italic>in vitro<\/jats:italic> 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-\u03b3 (IFN-\u03b3) 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\u201379) 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 <jats:italic>in vitro<\/jats:italic> 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 <jats:italic>ex vivo<\/jats:italic> 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.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009842","type":"journal-article","created":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T17:28:35Z","timestamp":1631813315000},"page":"e1009842","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":51,"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"],"prefix":"10.1371","volume":"17","author":[{"given":"Janna","family":"Heide","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Schulte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matin","family":"Kohsar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1737-161X","authenticated-orcid":true,"given":"Thomas Theo","family":"Brehm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5292-0795","authenticated-orcid":true,"given":"Marissa","family":"Herrmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2767-0405","authenticated-orcid":true,"given":"Hendrik","family":"Karsten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Marget","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Peine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4779-4648","authenticated-orcid":true,"given":"Alexandra M.","family":"Johansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7013-2250","authenticated-orcid":true,"given":"Alessandro","family":"Sette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9468-7944","authenticated-orcid":true,"given":"Marc","family":"L\u00fctgehetmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4843-4599","authenticated-orcid":true,"given":"William W.","family":"Kwok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Sidney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5033-1938","authenticated-orcid":true,"given":"Julian","family":"Schulze zur Wiesch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,9,16]]},"reference":[{"issue":"2","key":"ppat.1009842.ref001","doi-asserted-by":"crossref","first-page":"e16","DOI":"10.1016\/j.jinf.2020.04.021","article-title":"Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis","volume":"81","author":"Z Zheng","year":"2020","journal-title":"Journal of Infection"},{"key":"ppat.1009842.ref002","first-page":"914","article-title":"The Architecture of SARS-CoV-2","volume":"181","author":"D Kim","year":"2020","journal-title":"Transcriptome. 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