{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T06:16:45Z","timestamp":1792909005024,"version":"4.5.0"},"reference-count":74,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T00:00:00Z","timestamp":1619481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012308","name":"National Jewish Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012308","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The T cell antigens driving autoimmune Type 1 Diabetes (T1D) have been pursued for more than three decades. When diabetogenic CD4 T cell clones and their relevant MHCII antigen presenting alleles were first identified in rodents and humans, the path to discovering the peptide epitopes within pancreatic beta cell proteins seemed straightforward. However, as experimental results accumulated, definitive data were often absent or controversial. Work within the last decade has helped to clear up some of the controversy by demonstrating that a number of the important MHCII presented epitopes are not encoded in the natural beta cell proteins, but in fact are fusions between peptide fragments derived from the same or different proteins. Recently, the mechanism for generating these MHCII diabetogenic chimeric epitopes has been attributed to a form of reverse proteolysis, called transpeptidation, a process that has been well-documented in the production of MHCI presented epitopes. In this mini-review we summarize these data and their implications for T1D and other autoimmune responses.<\/jats:p>","DOI":"10.3389\/fimmu.2021.669986","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T05:49:23Z","timestamp":1619502563000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Hidden in Plain View: Discovery of Chimeric Diabetogenic CD4 T Cell Neo-Epitopes"],"prefix":"10.3389","volume":"12","author":[{"given":"Brendan K.","family":"Reed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Kappler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.20.8000","article-title":"Pancreatic islet-specific T-cell clones from nonobese diabetic mice","volume":"86","author":"Haskins","year":"1989","journal-title":"Proc Natl Acad Sci USA"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1006\/jaut.1994.1066","article-title":"Analysis of the spontaneous T cell response to insulin in NOD mice","volume":"7","author":"Wegmann","year":"1994","journal-title":"J Autoimmun"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830250430","article-title":"Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice","volume":"25","author":"Daniel","year":"1995","journal-title":"Eur J Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2337\/db07-1129","article-title":"On the pathogenicity of autoantigen-specific T-cell receptors","volume":"57","author":"Burton","year":"2008","journal-title":"Diabetes"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2007.11.005","article-title":"Insulin as an autoantigen in NOD\/human diabetes","volume":"20","author":"Zhang","year":"2008","journal-title":"Curr Opin Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2009.02.003","article-title":"Analysis of T cell receptor beta chains that combine with dominant conserved TRAV5D-4*04 anti-insulin B:9-23 alpha chains","volume":"33","author":"Zhang","year":"2009","journal-title":"J Autoimmun"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.10.6051","article-title":"The insulin-specific T cells of nonobese diabetic mice recognize a weak MHC-binding segment in more than one form","volume":"178","author":"Levisetti","year":"2007","journal-title":"J Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111502","article-title":"Register shifting of an insulin peptide-MHC complex allows diabetogenic T cells to escape thymic deletion","volume":"208","author":"Mohan","year":"2011","journal-title":"J Exp Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1416864111","article-title":"Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes","volume":"111","author":"Yang","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1716527115","article-title":"C-terminal modification of the insulin B:11\u201323 peptide creates superagonists in mouse and human type 1 diabetes","volume":"115","author":"Wang","year":"2018","journal-title":"Proc Natl Acad Sci"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/sciimmunol.aav7517","article-title":"How C-terminal additions to insulin B-chain fragments create superagonists for T cells in mouse and human type 1 diabetes","volume":"4","author":"Wang","year":"2019","journal-title":"Sci Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1016\/S1074-7613(00)80220-4","article-title":"Structural basis of peptide binding and presentation by the type I diabetes-associated MHC class II molecule of NOD mice","volume":"12","author":"Latek","year":"2000","journal-title":"Immunity"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1126\/science.288.5465.505","article-title":"A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes","volume":"288","author":"Corper","year":"2000","journal-title":"Science"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/88694","article-title":"Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes","volume":"2","author":"Lee","year":"2001","journal-title":"Nat Immunol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/sciimmunol.aaw6329","article-title":"Position beta57 of I-A(g7) controls early anti-insulin responses in NOD mice, linking an MHC susceptibility allele to type 1 diabetes onset","volume":"4","author":"Gioia","year":"2019","journal-title":"Sci Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1006545107","article-title":"Diabetogenic T cells recognize insulin bound to IAg7 in an unexpected, weakly binding register","volume":"107","author":"Stadinski","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25350","article-title":"Natural peptides selected by diabetogenic DQ8 and murine I-A(g7) molecules show common sequence specificity","volume":"115","author":"Suri","year":"2005","journal-title":"J Clin Invest"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110574","article-title":"Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope","volume":"208","author":"Daniel","year":"2011","journal-title":"J Exp Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1113954108","article-title":"Specificity and detection of insulin-reactive CD4+ T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse","volume":"108","author":"Crawford","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2776(05)87004-X","article-title":"Pathogenic T-cell clones in autoimmune diabetes: more lessons from the NOD mouse","volume":"87","author":"Haskins","year":"2005","journal-title":"Adv Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.2337\/diab.45.3.328","article-title":"Transfer of diabetes in the NOD-scid mouse by CD4 T-cell clones","volume":"45","author":"Peterson","year":"1996","journal-title":"Different Requirement CD8 T-cells Diabetes"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.2.908","article-title":"Identification of MHC class II-restricted peptide ligands, including a glutamic acid decarboxylase 65 sequence, that stimulate diabetogenic T cells from transgenic BDC2.5 nonobese diabetic mice","volume":"166","author":"Judkowski","year":"2001","journal-title":"J Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.8.4011","article-title":"Detection and characterization of T cells specific for BDC2.5 T cell-stimulating peptides","volume":"170","author":"You","year":"2003","journal-title":"J Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxf106","article-title":"Evidence for shared recognition of a peptide ligand by a diverse panel of non-obese diabetic mice-derived, islet-specific, diabetogenic T cell clones","volume":"14","author":"Yoshida","year":"2002","journal-title":"Int Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1844","article-title":"Chromogranin A is an autoantigen in type 1 diabetes","volume":"11","author":"Stadinski","year":"2010","journal-title":"Nat Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/0-306-46837-9_16","article-title":"and its derived peptides in the rat and porcine gastro-entero-pancreatic system","volume":"482","author":"Curry","year":"2000","journal-title":"Expression Localization Characterization Adv Exp Med Biol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s12026-012-8375-6","article-title":"Novel autoantigens for diabetogenic CD4 T cells in autoimmune diabetes","volume":"55","author":"Delong","year":"2013","journal-title":"Immunol Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.2337\/db12-0112","article-title":"Diabetogenic T-cell clones recognize an altered peptide of chromogranin A","volume":"61","author":"Delong","year":"2012","journal-title":"Diabetes"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1517862112","article-title":"N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes","volume":"112","author":"Jin","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.5.1386","article-title":"A diabetes-associated T-cell autoantigen maps to a telomeric locus on mouse chromosome 6","volume":"92","author":"Dallas-Pedretti","year":"1995","journal-title":"Proc Natl Acad Sci USA"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.10381\/nature10413","article-title":"Mouse genomic variation and its effect on phenotypes and gene regulation","volume":"477","author":"Keane","year":"2011","journal-title":"Nature"},{"key":"B32","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1152\/physrev.00042.2009","article-title":"Islet amyloid polypeptide, islet amyloid, and diabetes mellitus","volume":"91","author":"Westermark","year":"2011","journal-title":"Physiol Rev"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2016.10.007","article-title":"An insulin-IAPP hybrid peptide is an endogenous antigen for CD4 T cells in the non-obese diabetic mouse","volume":"78","author":"Wiles","year":"2017","journal-title":"J Autoimmun"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1172\/JCI1316","article-title":"Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies","volume":"101","author":"Schellekens","year":"1998","journal-title":"J Clin Invest"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1186\/ar93","article-title":"Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset","volume":"2","author":"Goldbach-Mansky","year":"2000","journal-title":"Arthritis Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keg184","article-title":"Anti-cyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis","volume":"42","author":"Bas","year":"2003","journal-title":"Rheumatol (Oxford)"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1196\/annals.1313.001","article-title":"Posttranslational modifications of self-antigens","volume":"1050","author":"Doyle","year":"2005","journal-title":"Ann N Y Acad Sci"},{"key":"B38","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1146\/annurev.immunol.18.1.53","article-title":"Molecular basis of celiac disease","volume":"18","author":"Sollid","year":"2000","journal-title":"Annu Rev Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/nature02240","article-title":"Immune recognition of a human renal cancer antigen through post-translational protein splicing","volume":"427","author":"Hanada","year":"2004","journal-title":"Nature"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1126\/science.1095522","article-title":"An antigenic peptide produced by peptide splicing in the proteasome","volume":"304","author":"Vigneron","year":"2004","journal-title":"Science"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/1941148a0","article-title":"Transpeptidation mechanism in blood clotting","volume":"194","author":"Lorand","year":"1962","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1126\/science.1097508","article-title":"Cell biology. Cutting and pasting antigenic peptides","volume":"304","author":"Cresswell","year":"2004","journal-title":"Science"},{"key":"B43","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.biocel.2008.08.036","article-title":"Transpeptidation and reverse proteolysis and their consequences for immunity","volume":"41","author":"Berkers","year":"2009","journal-title":"Int J Biochem Cell Biol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf4384","article-title":"A large fraction of HLA class I ligands are proteasome-generated spliced peptides","volume":"354","author":"Liepe","year":"2016","journal-title":"Science"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/sciimmunol.aar3947","article-title":"A subset of HLA-I peptides are not genomically templated: Evidence for cis- and trans-spliced peptide ligands","volume":"3","author":"Faridi","year":"2018","journal-title":"Sci Immunol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1084\/jem.20192135","article-title":"Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation","volume":"218","author":"Reed","year":"2021","journal-title":"J Exp Med"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad2791","article-title":"Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion","volume":"351","author":"Delong","year":"2016","journal-title":"Science"},{"key":"B48","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.jim.2018.08.011","article-title":"Development of T cell lines sensitive to antigen stimulation","volume":"462","author":"Williams","year":"2018","journal-title":"J Immunol Methods"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4203","article-title":"Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes","volume":"22","author":"Babon","year":"2016","journal-title":"Nat Med"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.2337\/dbi19-0022","article-title":"T-Cell Epitopes and Neo-epitopes in Type 1 Diabetes: A Comprehensive Update and Reappraisal","volume":"69","author":"James","year":"2020","journal-title":"Diabetes"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.2337\/db19-0620","article-title":"Hybrid Insulin Peptides Are Recognized by Human T Cells in the Context of DRB1*04:01","volume":"69","author":"Arribas-Layton","year":"2020","journal-title":"Diabetes"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.2337\/db19-0128","article-title":"Hybrid Insulin Peptides Are Autoantigens in Type 1 Diabetes","volume":"68","author":"Baker","year":"2019","journal-title":"Diabetes"},{"key":"B53","doi-asserted-by":"publisher","first-page":"e0200818","DOI":"10.1371\/journal.pone.0200818","article-title":"Heterogeneity of circulating CD8 T-cells specific to islet, neo-antigen and virus in patients with type 1 diabetes mellitus","volume":"13","author":"Laban","year":"2018","journal-title":"PloS One"},{"key":"B54","doi-asserted-by":"publisher","first-page":"48","DOI":"10.4049\/jimmunol.1900127","article-title":"Nanoparticles Containing an Insulin-ChgA Hybrid Peptide Protect from Transfer of Autoimmune Diabetes by Shifting the Balance between Effector T Cells and Regulatory T Cells","volume":"203","author":"Jamison","year":"2019","journal-title":"J Immunol"},{"key":"B55","doi-asserted-by":"publisher","first-page":"24032","DOI":"10.1038\/srep24032","article-title":"Proteasomes generate spliced epitopes by two different mechanisms and as efficiently as non-spliced epitopes","volume":"6","author":"Ebstein","year":"2016","journal-title":"Sci Rep"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2017.07.011","article-title":"Post-Translational Peptide Splicing and T Cell Responses","volume":"38","author":"Mishto","year":"2017","journal-title":"Trends Immunol"},{"key":"B57","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1038\/s41597-020-0487-6","article-title":"Large database for the analysis and prediction of spliced and non-spliced peptide generation by proteasomes","volume":"7","author":"Specht","year":"2020","journal-title":"Sci Data"},{"key":"B58","doi-asserted-by":"publisher","first-page":"e2000112","DOI":"10.1002\/pmic.202000112","article-title":"What We See, What We Do Not See, and What We Do Not Want to See in HLA Class I Immunopeptidomes","author":"Mishto","year":"2020","journal-title":"Proteomics"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1002\/bip.21422","article-title":"Circular proteins and mechanisms of cyclization","volume":"94","author":"Conlan","year":"2010","journal-title":"Biopolymers"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.20.14831","article-title":"Why does threonine, and not serine, function as the active site nucleophile in proteasomes","volume":"275","author":"Kisselev","year":"2000","journal-title":"J Biol Chem"},{"key":"B61","doi-asserted-by":"publisher","first-page":"994","DOI":"10.3390\/biom4040994","article-title":"Proteasome subtypes and regulators in the processing of antigenic peptides presented by class I molecules of the major histocompatibility complex","volume":"4","author":"Vigneron","year":"2014","journal-title":"Biomolecules"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.563800","article-title":"Elucidation of the Signatures of Proteasome-Catalyzed Peptide Splicing","volume":"11","author":"Paes","year":"2020","journal-title":"Front Immunol"},{"key":"B63","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/S0083-6729(08)00616-X","article-title":"Insulin granule biogenesis, trafficking and exocytosis","volume":"80","author":"Hou","year":"2009","journal-title":"Vitam Horm"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.1.141","article-title":"Role of beta-cell prohormone convertase (PC)1\/3 in processing of pro-islet amyloid polypeptide","volume":"53","author":"Marzban","year":"2004","journal-title":"Diabetes"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1042\/BC20050085","article-title":"Intracellular degradation of insulin and crinophagy are maintained by nitric oxide and cyclo-oxygenase 2 activity in isolated pancreatic islets","volume":"98","author":"Sandberg","year":"2006","journal-title":"Biol Cell"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0341-6","article-title":"Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides","volume":"560","author":"Wan","year":"2018","journal-title":"Nature"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-018-4592-4","article-title":"The resident macrophages in murine pancreatic islets are constantly probing their local environment, capturing beta cell granules and blood particles","volume":"61","author":"Zinselmeyer","year":"2018","journal-title":"Diabetologia"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.593348","article-title":"Emerging Roles of Exosomes in T1DM","volume":"11","author":"Pang","year":"2020","journal-title":"Front Immunol"},{"key":"B69","doi-asserted-by":"publisher","first-page":"a007765","DOI":"10.1101\/cshperspect.a007765","article-title":"Do MHCII-presented neoantigens drive type 1 diabetes and other autoimmune diseases","volume":"2","author":"Marrack","year":"2012","journal-title":"Cold Spring Harb Perspect Med"},{"key":"B70","doi-asserted-by":"publisher","first-page":"5369","DOI":"10.1038\/ncomms6369","article-title":"Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources","volume":"5","author":"Kim","year":"2014","journal-title":"Nat Commun"},{"key":"B71","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":"B72","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2018.08.011","article-title":"Selection of immunodominant epitopes during antigen processing is hierarchical","volume":"113","author":"Sadegh-Nasseri","year":"2019","journal-title":"Mol Immunol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25485","article-title":"Cathepsin L is essential for onset of autoimmune diabetes in NOD mice","volume":"115","author":"Maehr","year":"2005","journal-title":"J Clin Invest"},{"key":"B74","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.jaut.2009.07.003","article-title":"Roles for cathepsins S, L, and B in insulitis and diabetes in the NOD mouse","volume":"34","author":"Hsing","year":"2010","journal-title":"J Autoimmun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.669986\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T05:49:27Z","timestamp":1619502567000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.669986\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,27]]},"references-count":74,"alternative-id":["10.3389\/fimmu.2021.669986"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.669986","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,27]]},"article-number":"669986"}}