{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T09:46:01Z","timestamp":1785059161806,"version":"3.55.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T00:00:00Z","timestamp":1693785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>In this study, we report a novel therapeutic approach using B lymphocytes to attract islet-specific T cells in the non-obese diabetic (NOD) mouse model and prevent the development of autoimmune diabetes. Rather than using the antibody receptor of B cells, this approach utilizes their properties as antigen-presenting cells to T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Purified splenic B cells were treated with lipopolysaccharide, which increases regulatory B (Breg) cell function, then electroporated with mRNA encoding either chimeric MHC-I or MHC-II molecules covalently linked to antigenic peptides. Immunoregulatory functions of these engineered B cells (e-B cells) were tested by <jats:italic>in vitro<\/jats:italic> assays and <jats:italic>in vivo<\/jats:italic> co-transfer experiments with beta-cell-antigen-specific CD8<jats:sup>+<\/jats:sup> or CD4<jats:sup>+<\/jats:sup> T cells in NOD.Scid mice, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The e-B cells expressing chimeric MHC-I-peptide inhibited antigen-specific CD8<jats:sup>+<\/jats:sup> T-cell cytotoxicity <jats:italic>in vitro<\/jats:italic>. The e-B cells expressing chimeric MHC-II-peptide induced antigen-specific CD4<jats:sup>+<\/jats:sup> T cells to express the regulatory markers, PD-1, ICOS, CTLA-4, Lag3, and Nrp1. Furthermore, e-B cells encoding the chimeric MHC-I and MHC-II peptide constructs protected NOD.Scid mice from autoimmune diabetes induced by transfer of antigen-specific CD8<jats:sup>+<\/jats:sup> and CD4<jats:sup>+<\/jats:sup> T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>MHC\u2013peptide chimeric e-B cells interacted with pathogenic T cells, and protected the host from autoimmune diabetes, in a mouse model. Thus, we have successfully expressed MHC\u2013peptide constructs in B cells that selectively targeted antigen-specific cells, raising the possibility that this strategy could be used to endow different protective cell types to specifically regulate\/remove pathogenic cells.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1227133","type":"journal-article","created":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T08:13:45Z","timestamp":1693815225000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Novel engineered B lymphocytes targeting islet-specific T cells inhibit the development of type 1 diabetes in non-obese diabetic Scid mice"],"prefix":"10.3389","volume":"14","author":[{"given":"Dawei","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitri","family":"Kakabadse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigal","family":"Fishman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadas","family":"Weinstein-Marom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Boldison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terri C.","family":"Thayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gideon","family":"Gross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. Susan","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI94549","article-title":"Autoreactive T cells in type 1 diabetes","volume":"127","author":"Pugliese","year":"2017","journal-title":"J Clin Invest"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2015.10","article-title":"The multifaceted role of CD4(+) T cells in CD8(+) T cell memory","volume":"16","author":"Laidlaw","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.6285","article-title":"Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children","volume":"309","author":"Ziegler","year":"2013","journal-title":"JAMA"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-0626","article-title":"B-lymphocyte depletion with rituximab and \u03b2-cell function: two-year results","volume":"37","author":"Pescovitz","year":"2014","journal-title":"Diabetes Care"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0904452","article-title":"Rituximab, B-lymphocyte depletion, and preservation of beta-cell function","volume":"361","author":"Pescovitz","year":"2009","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI32405","article-title":"Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice","volume":"117","author":"Hu","year":"2007","journal-title":"J Clin Invest"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116835","article-title":"Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients","volume":"92","author":"Itoh","year":"1993","journal-title":"J Clin Invest"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.2337\/db15-1615","article-title":"Differential Insulitic Profiles Determine the Extent of beta-Cell Destruction and the Age at Onset of Type 1 Diabetes","volume":"65","author":"Leete","year":"2016","journal-title":"Diabetes"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.2.1081","article-title":"Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice","volume":"167","author":"Tian","year":"2001","journal-title":"J Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(02)00274-1","article-title":"Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation","volume":"16","author":"Mizoguchi","year":"2002","journal-title":"Immunity"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/ni833","article-title":"B cells regulate autoimmunity by provision of IL-10","volume":"3","author":"Fillatreau","year":"2002","journal-title":"Nat Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nature12979","article-title":"IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases","volume":"507","author":"Shen","year":"2014","journal-title":"Nature"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.746187","article-title":"Regulatory B cells: role in type 1 diabetes","volume":"12","author":"Boldison","year":"2021","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.611795","article-title":"Immunosuppressive mechanisms of regulatory B cells","volume":"12","author":"Catalan","year":"2021","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.2337\/db13-1639","article-title":"Interleukin-10+ regulatory B cells arise within antigen-experienced CD40+ B cells to maintain tolerance to islet autoantigens","volume":"64","author":"Kleffel","year":"2015","journal-title":"Diabetes"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.565236","article-title":"Cancer immunotherapy using chimeric antigen receptor expressing T-cells: present and future needs of clinical cancer centers","volume":"11","author":"Gotti","year":"2020","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"102289","DOI":"10.1016\/j.jaut.2019.05.017","article-title":"Regulatory T cells engineered with a novel insulin-specific chimeric antigen receptor as a candidate immunotherapy for type 1 diabetes","volume":"103","author":"Tenspolde","year":"2019","journal-title":"J Autoimmun"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2018.08.004","article-title":"Chimeric antigen receptor (CAR) T cells targeting a pathogenic MHC class II:peptide complex modulate the progression of autoimmune diabetes","volume":"96","author":"Zhang","year":"2019","journal-title":"J Autoimmun"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1101\/2023.02.23.529737","article-title":"Insulin B peptide-MHC class II-specific chimeric antigen receptor-Tregs prevent autoimmune diabetes","author":"Spanier","year":"2023","journal-title":"bioRxiv"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2010.08.005","article-title":"Immunotargeting of insulin reactive CD8 T cells to prevent diabetes","volume":"35","author":"Scott","year":"2010","journal-title":"J Autoimmun"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2016.12.007","article-title":"Adoptive Transfer of mRNA-Transfected T Cells Redirected against Diabetogenic CD8 T Cells Can Prevent Diabetes","volume":"25","author":"Fishman","year":"2017","journal-title":"Mol Ther"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abo0777","article-title":"Antigen-specific depletion of CD4(+) T cells by CAR T cells reveals distinct roles of higher- and lower-affinity TCRs during autoimmunity","volume":"7","author":"Yi","year":"2022","journal-title":"Sci Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90730-E","article-title":"Following a diabetogenic T cell from genesis through pathogenesis","volume":"74","author":"Katz","year":"1993","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.2337\/db08-0800","article-title":"Activation of insulin-reactive CD8 T-cells for development of autoimmune diabetes","volume":"58","author":"Wong","year":"2009","journal-title":"Diabetes"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-018-4597-z","article-title":"B cell depletion reduces T cell activation in pancreatic islets in a murine autoimmune diabetes model","volume":"61","author":"Da Rosa","year":"2018","journal-title":"Diabetologia"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxg136","article-title":"Chimeric beta2 microglobulin\/CD3zeta polypeptides expressed in T cells convert MHC class I peptide ligands into T cell activation receptors: a potential tool for specific targeting of pathogenic CD8(+) T cells","volume":"15","author":"Margalit","year":"2003","journal-title":"Int Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.4.2116","article-title":"Membrane-anchored beta 2-microglobulin stabilizes a highly receptive state of MHC class I molecules","volume":"174","author":"Berko","year":"2005","journal-title":"J Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.1.217","article-title":"Induction of antitumor immunity by CTL epitopes genetically linked to membrane-anchored beta2-microglobulin","volume":"176","author":"Margalit","year":"2006","journal-title":"J Immunol"},{"key":"B29","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":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12340","article-title":"Selective immunotargeting of diabetogenic CD4 T cells by genetically redirected T cells","volume":"143","author":"Perez","year":"2014","journal-title":"Immunology"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/12465","article-title":"Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library","volume":"5","author":"Wong","year":"1999","journal-title":"Nat Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1126\/science.2205920","article-title":"Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone","volume":"249","author":"Haskins","year":"1990","journal-title":"Science"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2012.60","article-title":"Regulatory B cells in autoimmune diseases","volume":"10","author":"Yang","year":"2013","journal-title":"Cell Mol Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.592914","article-title":"Advances of regulatory B cells in autoimmune diseases","volume":"12","author":"Zhu","year":"2021","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.09.070","article-title":"Transcriptomics identify CD9 as a marker of murine IL-10-competent regulatory B cells","volume":"13","author":"Sun","year":"2015","journal-title":"Cell Rep"},{"key":"B36","doi-asserted-by":"publisher","first-page":"395","DOI":"10.2337\/db07-0589","article-title":"Marginal-zone B-cells of nonobese diabetic mice expand with diabetes onset, invade the pancreatic lymph nodes, and present autoantigen to diabetogenic T-cells","volume":"57","author":"Marino","year":"2008","journal-title":"Diabetes"},{"key":"B37","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1111\/imr.12964","article-title":"Novel frontiers in regulatory B cells","volume":"299","author":"Mauri","year":"2021","journal-title":"Immunol Rev"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.04.005","article-title":"Regulatory B cells: origin, phenotype, and function","volume":"42","author":"Rosser","year":"2015","journal-title":"Immunity"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.2337\/diab.46.7.1124","article-title":"Inhibition of diabetes by an insulin-reactive CD4 T-cell clone in the nonobese diabetic mouse","volume":"46","author":"Zekzer","year":"1997","journal-title":"Diabetes"},{"key":"B40","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/ni.1731","article-title":"The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation","volume":"10","author":"Koch","year":"2009","journal-title":"Nat Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01453-w","article-title":"IFNgamma-induction of T(H)1-like regulatory T cells controls antiviral responses","volume":"24","author":"Gocher-Demske","year":"2023","journal-title":"Nat Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.2337\/db20-1170","article-title":"Tolerogenic delivery of a hybrid insulin peptide markedly prolongs islet graft survival in the NOD mouse","volume":"71","author":"Jamison","year":"2022","journal-title":"Diabetes"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.2337\/db12-0006","article-title":"B-cell cross-presentation of autologous antigen precipitates diabetes","volume":"61","author":"Marino","year":"2012","journal-title":"Diabetes"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-019-0324-z","article-title":"Dendritic cells license regulatory B cells to produce IL-10 and mediate suppression of antigen-specific CD8 T cells","volume":"17","author":"Boldison","year":"2020","journal-title":"Cell Mol Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1227133\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T08:13:49Z","timestamp":1693815229000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1227133\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,4]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2023.1227133"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1227133","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,4]]},"article-number":"1227133"}}