{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T06:03:32Z","timestamp":1784527412915,"version":"3.55.0"},"reference-count":93,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Epitope-specific T cells provide significant long-lived protection afforded by adaptive immunity to SARS-CoV-2 spike. CD4+ T-cell epitope peptides that are generated by non-ATP-dependent antigen-processing proteases bind with modest specificity to MHC class II molecules in the endo-lysosome. Studies document the influence of antigen-presenting cell type, manner of endocytosis, and antigen conformation on the strength of CD4+ T-cell response.  Nevertheless, few studies report changes in epitope dominance due to circumstances of antigen exposure, which could shape proteolytic antigen processing in the class-II pathway because conformational domains limit proteolysis or MHCII binding.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Processing of SARS-CoV-2 spike was modeled using limited proteolysis of soluble spike trimer, and the effect of spike conformation on CD4+ T-cell epitope dominance was analyzed using IL-2 Elispots responding to two nine-peptide pools from conformationally stable and unstable regions of spike.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Protease-sensitive sites coincided with domain boundaries and other conformationally unstable regions, confirming that structure limits proteolysis.  The ratio of CD4+ T-cell response to stable and unstable peptide pools in two non-hospitalized human subjects cohorts distinguished whether exposure was by infection or vaccination.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Circumstances of exposure to spike, e.g., spike mRNA vaccination or SARS-CoV-2 infection, could influence populations of antigen presenting cells and their levels of activation, resulting in different patterns of spike fragmentation, peptide loading, and T-cell response.  Circumstances of exposure also affect spike conformational changes that contribute to distinct dominance patterns.  Thus, epitope dominance patterns potentially indicate exposure history, immune imprinting, and potentially the protectiveness of the CD4+ T-cell response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1857103","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T05:34:21Z","timestamp":1784525661000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Conformational bias in SARS-CoV-2 Spike CD4+ T-cell epitope dominance"],"prefix":"10.3389","volume":"17","author":[{"given":"Samuel J.","family":"Landry","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tulane University School of Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. Kalaya","family":"Steede","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tulane University School of Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Tiomkin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tulane University School of Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Tulane University School of Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramgopal R.","family":"Mettu","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Tulane University, New Orleans, Louisiana, United States, Tulane University School of Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loren","family":"Gragert","sequence":"additional","affiliation":[{"name":"Department of Medicine, Tulane University School Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith H.","family":"Aberle","sequence":"additional","affiliation":[{"name":"Center for Virology, Medical University of Vienna","place":["Vienna, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J.","family":"Zwezdaryk","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Tulane University School of Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Medicine, Tulane University School of Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay K.","family":"Kolls","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Tulane University School of Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bronwyn M.","family":"Gunn","sequence":"additional","affiliation":[{"name":"Paul G. Allen School of Global Health, Washington State University","place":["Pullman, WA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelie E.","family":"Murrell","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Tulane University School of Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivy V.","family":"Trinh","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Tulane University School of Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Schieffelin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Tulane University School of Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Tulane University School of Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth B.","family":"Norton","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Tulane University School of Medicine","place":["New Orleans, LA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.08.008","article-title":"SARS-CoV-2-specific T cells in the changing landscape of the COVID-19 pandemic","volume":"55","author":"Bertoletti","year":"2022","journal-title":"Immunity"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07748-8","article-title":"Immunological memory diversity in the human upper airway","volume":"632","author":"Ramirez","year":"2024","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.09.016","article-title":"ACTIVating resources for the COVID-19 pandemic: In vivo models for vaccines and therapeutics","volume":"28","author":"Hewitt","year":"2020","journal-title":"Cell Host Microbe"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-03041-6","article-title":"Correlates of protection against SARS-CoV-2 in rhesus macaques","volume":"590","author":"McMahan","year":"2021","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"E20","DOI":"10.1038\/s41586-024-08519-1","article-title":"Author correction: Immunological memory diversity in the human upper airway","volume":"637","author":"Ramirez","year":"2025","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd4570","article-title":"Inborn errors of type I IFN immunity in patients with life-threatening COVID-19","volume":"370","author":"Zhang","year":"2020","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41590-023-01700-0","article-title":"BCG vaccination stimulates integrated organ immunity by feedback of the adaptive immune response to imprint prolonged innate antiviral resistance","volume":"25","author":"Lee","year":"2024","journal-title":"Nat Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03278-y","article-title":"SARS-CoV-2-specific plasma cells are not durably established in the bone marrow long-lived compartment after mRNA vaccination","volume":"31","author":"Nguyen","year":"2024","journal-title":"Nat Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0782-6","article-title":"Broad and strong memory CD4(+) and CD8(+) T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19","volume":"21","author":"Peng","year":"2020","journal-title":"Nat Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-01787-z","article-title":"Antibody-independent protection against heterologous SARS-CoV-2 challenge conferred by prior infection or vaccination","volume":"25","author":"Fumagalli","year":"2024","journal-title":"Nat Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41590-020-00808-x","article-title":"SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition","volume":"22","author":"Nelde","year":"2021","journal-title":"Nat Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1101\/2021.12.28.474333","article-title":"SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from Alpha to Omicron","volume":"185","author":"Tarke","year":"2022","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01700-x","article-title":"Ancestral SARS-CoV-2-specific T cells cross-recognize the Omicron variant","volume":"28","author":"Gao","year":"2022","journal-title":"Nat Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1126\/science.abq1841","article-title":"Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure","volume":"377","author":"Reynolds","year":"2022","journal-title":"Science"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.1016\/j.cell.2022.01.029","article-title":"T cell reactivity to the SARS-CoV-2 Omicron variant is preserved in most but not all individuals","volume":"185","author":"Naranbhai","year":"2022","journal-title":"Cell"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04465-y","article-title":"Vaccines elicit highly conserved cellular immunity to SARS-CoV-2 Omicron","volume":"603","author":"Liu","year":"2022","journal-title":"Nature"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04460-3","article-title":"T cell responses to SARS-CoV-2 spike cross-recognize Omicron","volume":"603","author":"Keeton","year":"2022","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.03.005","article-title":"Spheromers reveal robust T cell responses to the Pfizer\/BioNTech vaccine and attenuated peripheral CD8(+) T cell responses post SARS-CoV-2 infection","volume":"56","author":"Gao","year":"2023","journal-title":"Immunity"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adh0687","article-title":"SARS-CoV-2 vaccination enhances the effector qualities of spike-specific T cells induced by COVID-19","volume":"8","author":"Cai","year":"2023","journal-title":"Sci Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2022.04.014","article-title":"A dual-antigen self-amplifying RNA SARS-CoV-2 vaccine induces potent humoral and cellular immune responses and protects against SARS-CoV-2 variants through T cell-mediated immunity","volume":"30","author":"McCafferty","year":"2022","journal-title":"Mol Ther"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1109438108","article-title":"Affinity maturation of human CD4 by yeast surface display and crystal structure of a CD4-HLA-DR1 complex","volume":"108","author":"Wang","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.122.321116","article-title":"Immunodominant MHC-II (Major Histocompatibility Complex II) restricted epitopes in human apolipoprotein B","volume":"131","author":"Roy","year":"2022","journal-title":"Circ Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.6.3206","article-title":"Independent selection by I-Ak molecules of two epitopes found in tandem in an extended polypeptide antigen [In Process Citation","volume":"165","author":"Gugasyan","year":"2000","journal-title":"J Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/364033a0","article-title":"3-dimensional structure of the human class-II histocompatibility antigen HLA-DR1","volume":"364","author":"Brown","year":"1993","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.23.021704.115658","article-title":"How TCRs bind MHCs, peptides, and coreceptors","volume":"24","author":"Rudolph","year":"2006","journal-title":"Annu Rev Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(04)00073-1","article-title":"T cells distinguish MHC-peptide complexes formed in separate vesicles and edited by H2-DM","volume":"20","author":"Pu","year":"2004","journal-title":"Immunity"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902493","article-title":"New design of MHC class II tetramers to accommodate fundamental principles of antigen presentation","volume":"183","author":"Landais","year":"2009","journal-title":"J Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens8040220","article-title":"Peptide epitope hot spots of CD4 T cell recognition within influenza hemagglutinin during the primary response to infection","volume":"8","author":"Knowlden","year":"2019","journal-title":"Pathogens"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/s0167-5699(97)01152-3","article-title":"Local protein instability predictive of helper T-cell epitopes","volume":"18","author":"Landry","year":"1997","journal-title":"Immunol Today"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.071063898","article-title":"Localization of CD4+ T cell epitope hotspots to exposed strands of HIV envelope glycoprotein suggests structural influences on antigen processing","volume":"98","author":"Surman","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200738011","article-title":"Antigen structure influences helper T-cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120","volume":"38","author":"Mirano-Bascos","year":"2008","journal-title":"Eur J Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2015.04.082","article-title":"Conformational instability governed by disulfide bonds partitions the dominant from subdominant helper T-cell responses specific for HIV-1 envelope glycoprotein gp120","volume":"33","author":"Nguyen","year":"2015","journal-title":"Vaccine"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20200206","article-title":"Deciphering and predicting CD4+ T cell immunodominance of influenza virus hemagglutinin","volume":"217","author":"Cassotta","year":"2020","journal-title":"J Exp Med"},{"key":"B34","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.jim.2016.02.013","article-title":"CD4+ T-cell epitope prediction using antigen processing constraints","volume":"432","author":"Mettu","year":"2016","journal-title":"J Immunol Methods"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.2c00237","article-title":"CD4+ T-cell epitope prediction by combined analysis of antigen conformational flexibility and peptide-MHCII binding affinity","volume":"61","author":"Charles","year":"2022","journal-title":"Biochemistry"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.2210\/pdb6xr8\/pdb","article-title":"Distinct conformational states of SARS-CoV-2 spike protein","volume":"369","author":"Cai","year":"2020","journal-title":"Science"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2111199119","article-title":"SARS-CoV-2 spike engagement of ACE2 primes S2' site cleavage and fusion initiation","volume":"119","author":"Yu","year":"2022","journal-title":"Proc Natl Acad Sci USA"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-020-0479-4","article-title":"Controlling the SARS-CoV-2 spike glycoprotein conformation","volume":"27","author":"Henderson","year":"2020","journal-title":"Nat Struct Mol Biol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2025.01.008","article-title":"Identification of indirect CD4(+) T cell epitopes associated with transplant rejection provides a target for donor-specific tolerance induction","volume":"58","author":"Zhanzak","year":"2025","journal-title":"Immunity"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.12.7849","article-title":"Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells","volume":"178","author":"Kang","year":"2007","journal-title":"J Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1172\/jci75894","article-title":"HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial","volume":"124","author":"Bart","year":"2014","journal-title":"J Clin Invest"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.7554\/elife.99173","article-title":"PRR adjuvants restrain high stability peptides presentation on APCs","volume":"13","author":"Li","year":"2024","journal-title":"Elife"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2015.01506","article-title":"CD4+ T cells targeting dominant and cryptic epitopes from Bacillus anthracis lethal factor","volume":"6","author":"Ascough","year":"2015","journal-title":"Front Microbiol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1101\/2024.08.21.608923","article-title":"Aging and viral evolution impair immunity against dominant pan-coronavirus-reactive T cell epitope","volume":"55","author":"Loyal","year":"2025","journal-title":"Eur J Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20211327","article-title":"Identification of conserved SARS-CoV-2 spike epitopes that expand public cTfh clonotypes in mild COVID-19 patients","volume":"218","author":"Lu","year":"2021","journal-title":"J Exp Med"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1126\/science.abh1823","article-title":"Cross-reactive CD4(+) T cells enhance SARS-CoV-2 immune responses upon infection and vaccination","volume":"374","author":"Loyal","year":"2021","journal-title":"Science"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1083\/jcb1745oia9","article-title":"Enhancing immunogenicity by limiting susceptibility to lysosomal proteolysis","volume":"203","author":"Delamarre","year":"2006","journal-title":"J Exp Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1126\/science.1108003","article-title":"Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate","volume":"307","author":"Delamarre","year":"2005","journal-title":"Science"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1126\/science.1080106","article-title":"Activation of lysosomal function during dendritic cell maturation","volume":"299","author":"Trombetta","year":"2003","journal-title":"Science"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02078-6","article-title":"Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection","volume":"29","author":"Mentzer","year":"2023","journal-title":"Nat Med"},{"key":"B51","doi-asserted-by":"publisher","first-page":"4031","DOI":"10.1038\/s41467-024-48339-5","article-title":"Relationship between HLA genetic variations, COVID-19 vaccine antibody response, and risk of breakthrough outcomes","volume":"15","author":"Xie","year":"2024","journal-title":"Nat Commun"},{"key":"B52","doi-asserted-by":"publisher","first-page":"100204","DOI":"10.1101\/2020.12.08.416750","article-title":"Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases","volume":"2","author":"Tarke","year":"2021","journal-title":"Cell Rep Med"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.21417\/jsl2021s","article-title":"Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2","volume":"372","author":"Low","year":"2021","journal-title":"Science"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110952","article-title":"Broadly recognized, cross-reactive SARS-CoV-2 CD4 T cell epitopes are highly conserved across human coronaviruses and presented by common HLA alleles","volume":"39","author":"Becerra-Artiles","year":"2022","journal-title":"Cell Rep"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1410","article-title":"High-resolution analysis of individual spike peptide-specific CD4(+) T-cell responses in vaccine recipients and COVID-19 patients","volume":"11","author":"Karsten","year":"2022","journal-title":"Clin Transl Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1092","article-title":"The immune epitope database (IEDB): 2024 update","volume":"53","author":"Vita","year":"2025","journal-title":"Nucleic Acids Res"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.11.032","article-title":"Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein","volume":"181","author":"Walls","year":"2020","journal-title":"Cell"},{"key":"B58","doi-asserted-by":"publisher","first-page":"108454","DOI":"10.2139\/ssrn.3671736","article-title":"The human leukocyte antigen class II immunopeptidome of the SARS-coV-2 spike glycoprotein","volume":"33","author":"Knierman","year":"2020","journal-title":"Cell Rep"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113596","article-title":"The HLA-II immunopeptidome of SARS-coV-2","volume":"43","author":"Weingarten-Gabbay","year":"2024","journal-title":"Cell Rep"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.3c00335","article-title":"Structural framework for analysis of CD4+ T-cell epitope dominance in viral fusion proteins","volume":"62","author":"Landry","year":"2023","journal-title":"Biochemistry"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb2507","article-title":"Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation","volume":"367","author":"Wrapp","year":"2020","journal-title":"Science"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd0826","article-title":"Structure-based design of prefusion-stabilized SARS-CoV-2 spikes","volume":"369","author":"Hsieh","year":"2020","journal-title":"Science"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.6.2618","article-title":"A role for cathepsin L and cathepsin S in peptide generation for MHC class II presentation","volume":"168","author":"Hsieh","year":"2002","journal-title":"J Immunol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb9983","article-title":"Site-specific glycan analysis of the SARS-CoV-2 spike","volume":"369","author":"Watanabe","year":"2020","journal-title":"Science"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108630","article-title":"D614G mutation alters SARS-CoV-2 spike conformation and enhances protease cleavage at the S1\/S2 junction","volume":"34","author":"Gobeil","year":"2021","journal-title":"Cell Rep"},{"key":"B66","doi-asserted-by":"publisher","first-page":"3618","DOI":"10.1038\/s41467-020-17371-6","article-title":"Cryo-EM analysis of the post-fusion structure of the SARS-CoV spike glycoprotein","volume":"11","author":"Fan","year":"2020","journal-title":"Nat Commun"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.3390\/cells1020127","article-title":"Dissecting the T cell response: Proliferation assays vs. cytokine signatures by ELISPOT","volume":"1","author":"Anthony","year":"2012","journal-title":"Cells"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3390\/v14071570","article-title":"Omicron BA.1 mutations in SARS-CoV-2 spike lead to reduced T-cell response in vaccinated and convalescent individuals","volume":"14","author":"Emmelot","year":"2022","journal-title":"Viruses"},{"key":"B69","doi-asserted-by":"publisher","first-page":"2022.04.22.22274032","DOI":"10.1101\/2022.04.22.22274032","article-title":"Antibody responses in non-severe SARS-CoV-2 infections are driven by CD4+ T cells and age","author":"Murrell","year":"2022","journal-title":"medRxiv"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.mchd-0008-2015","article-title":"Antigen processing and presentation mechanisms in myeloid cells","volume":"4","author":"Roche","year":"2016","journal-title":"Microbiol Spectr"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-041015-055420","article-title":"Variations in MHC class II antigen processing and presentation in health and disease","volume":"34","author":"Unanue","year":"2016","journal-title":"Annu Rev Immunol"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2021.06.003","article-title":"New insights into B cells as antigen presenting cells","volume":"70","author":"Ghosh","year":"2021","journal-title":"Curr Opin Immunol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01175-5","article-title":"Establishment and recall of SARS-CoV-2 spike epitope-specific CD4(+) T cell memory","volume":"23","author":"Wragg","year":"2022","journal-title":"Nat Immunol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902749","article-title":"T cell epitope specificity and pathogenesis of mouse hepatitis virus-1-induced disease in susceptible and resistant hosts","volume":"185","author":"Khanolkar","year":"2010","journal-title":"J Immunol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00016","article-title":"CD4 T cell determinants in West Nile virus disease and asymptomatic infection","volume":"11","author":"Koblischke","year":"2020","journal-title":"Front Immunol"},{"key":"B76","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1053\/j.gastro.2012.12.002","article-title":"A dominant CD4(+) T-cell response to Helicobacter pylori reduces risk for gastric disease in humans","volume":"144","author":"Chen","year":"2013","journal-title":"Gastroenterology"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2006.06.014","article-title":"Antigen three-dimensional structure guides the processing and presentation of helper T-cell epitopes","volume":"44","author":"Carmicle","year":"2006","journal-title":"Mol Immunol"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(00)80176-4","article-title":"Proteolysis in MHC class II antigen presentation: Who's in charge","volume":"12","author":"Villadangos","year":"2000","journal-title":"Immunity"},{"key":"B79","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1186\/s13073-025-01577-8","article-title":"Cut or bind? Antigen-specific processing mechanisms define CD4(+) T cell immunodominant epitopes for SARS-CoV-2 S and N proteins","volume":"17","author":"Alvaro-Benito","year":"2025","journal-title":"Genome Med"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2015.07.018","article-title":"Exogenous antigens bind MHC class II first, and are processed by cathepsins later","volume":"68","author":"Sadegh-Nasseri","year":"2015","journal-title":"Mol Immunol"},{"key":"B81","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/s41541-023-00801-z","article-title":"MVA-based vaccine candidates encoding the native or prefusion-stabilized SARS-CoV-2 spike reveal differential immunogenicity in humans","volume":"9","author":"Mayer","year":"2024","journal-title":"NPJ Vaccines"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01330-9","article-title":"Safety and immunogenicity of the SARS-CoV-2 BNT162b1 mRNA vaccine in younger and older Chinese adults: A randomized, placebo-controlled, double-blind phase 1 study","volume":"27","author":"Li","year":"2021","journal-title":"Nat Med"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.11.004","article-title":"Cryo-EM structures of SARS-CoV-2 spike without and with ACE2 reveal a pH-dependent switch to mediate endosomal positioning of receptor-binding domains","volume":"28","author":"Zhou","year":"2020","journal-title":"Cell Host Microbe"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1166924","article-title":"A novel precision-serology assay for SARS-CoV-2 infection based on linear B-cell epitopes of spike protein","volume":"14","author":"Lundin","year":"2023","journal-title":"Front Immunol"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-021-00681-2","article-title":"Single-cell RNA sequencing of blood antigen-presenting cells in severe COVID-19 reveals multi-process defects in antiviral immunity","volume":"23","author":"Saichi","year":"2021","journal-title":"Nat Cell Biol"},{"key":"B86","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1038\/s41467-023-36140-9","article-title":"Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2","volume":"14","author":"Venet","year":"2023","journal-title":"Nat Commun"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108234","article-title":"Evasion of type I interferon by SARS-CoV-2","volume":"33","author":"Xia","year":"2020","journal-title":"Cell Rep"},{"key":"B88","doi-asserted-by":"publisher","first-page":"3810","DOI":"10.1038\/s41467-020-17665-9","article-title":"Activation and evasion of type I interferon responses by SARS-CoV-2","volume":"11","author":"Lei","year":"2020","journal-title":"Nat Commun"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1021\/bi00558a014","article-title":"Limited proteolysis of pig heart citrate synthase by subtilisin, chymotrypsin, and trypsin","volume":"19","author":"Bloxham","year":"1980","journal-title":"Biochemistry"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m107624200","article-title":"Proteolytic sensitivity and helper T-cell epitope immunodominance associated with the mobile loop in Hsp10s","volume":"277","author":"Carmicle","year":"2002","journal-title":"J Biol Chem"},{"key":"B91","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/s41421-022-00419-w","article-title":"Novel cleavage sites identified in SARS-CoV-2 spike protein reveal mechanism for cathepsin L-facilitated viral infection and treatment strategies","volume":"8","author":"Zhao","year":"2022","journal-title":"Cell Discov"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2009.10.052","article-title":"Naturally processed T cell-activating peptides of the major birch pollen allergen","volume":"125","author":"Mutschlechner","year":"2010","journal-title":"J Allergy Clin Immunol"},{"key":"B93","volume-title":"Coronavirus disease 2019 (COVID-19) 2021 case definition","year":"2021"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1857103\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T05:34:22Z","timestamp":1784525662000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1857103\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":93,"alternative-id":["10.3389\/fimmu.2026.1857103"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1857103","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]},"article-number":"1857103"}}