{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T02:48:41Z","timestamp":1772246921654,"version":"3.50.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T00:00:00Z","timestamp":1656547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    We generated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell lines (TCLs) reactive to either SARS-CoV-2 spike (S) or membrane (M) proteins from unexposed na\u00efve T cells from six healthy donor volunteers to understand in fine detail whether the S and M structural proteins have intrinsic differences in driving antigen-specific CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses. Having shown that each of the TCLs were antigen-specific and antigen-reactive, single cell mRNA analyses demonstrated that SARS-CoV-2 S and M proteins drive strikingly distinct molecular signatures. Whereas the S-specific CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell transcriptional signature showed a marked upregulation of CCL1, CD44, IL17RB, TNFRSF18 (GITR) and IGLC3 genes, in general their overall transcriptome signature was more similar to CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses induced by other viral antigens (e.g. CMV). However, the M protein-specific CD4\n                    <jats:sup>+<\/jats:sup>\n                    TCLs have a transcriptomic signature that indicate a marked suppression of interferon signaling, characterized by a downregulation of the genes encoding ISG15, IFITM1, IFI6, MX1, STAT1, OAS1, IFI35, IFIT3 and IRF7 (a molecular signature which is not dissimilar to that found in severe COVID-19). Our study suggests a potential link between the antigen specificity of the SARS-CoV-2-reactive CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and the development of specific sets of adaptive immune responses. Moreover, the balance between T cells of significantly different specificities may be the key to understand how CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell dysregulation can determine the clinical outcomes of COVID-19.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.883159","type":"journal-article","created":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T01:18:24Z","timestamp":1656551904000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Antigenic Determinants of SARS-CoV-2-Specific CD4+ T Cell Lines Reveals M Protein-Driven Dysregulation of Interferon Signaling"],"prefix":"10.3389","volume":"13","author":[{"given":"Pedro H.","family":"Gazzinelli-Guimaraes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gayatri","family":"Sanku","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Sette","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Weiskopf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Schaughency","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Lack","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas B.","family":"Nutman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-020-00459-7","article-title":"Characteristics of SARS-CoV-2 and COVID-19","volume":"19","author":"Hu","year":"2021","journal-title":"Nat Rev Microbiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"66","DOI":"10.15698\/cst2020.04.216","article-title":"Coronavirus Infections: Epidemiological, Clinical and Immunological Features and Hypotheses","volume":"4","author":"Raoult","year":"2020","journal-title":"Cell Stress"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2550-z","article-title":"SARS-CoV-2-Specific T Cell Immunity in Cases of COVID-19 and SARS, and Uninfected Controls","volume":"584","author":"Le 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