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Immunol."],"abstract":"<jats:p>Systemic delivery of nanoparticles (NPs) coated with mono-specific autoimmune disease-relevant peptide-major histocompatibility complex class II (pMHCII) molecules can resolve organ inflammation in various disease models in a disease-specific manner without impairing normal immunity. These compounds invariably trigger the formation and systemic expansion of cognate pMHCII-specific T-regulatory type 1 (TR1) cells. By focusing on type 1 diabetes (T1D)-relevant pMHCII-NP types that display an epitope from the insulin B-chain bound to the same MHCII molecule (IA<jats:sup>g7<\/jats:sup>) on three different registers, we show that pMHCII-NP-induced TR1 cells invariably co-exist with cognate T-Follicular Helper (TFH)-like cells of quasi-identical clonotypic composition and are oligoclonal, yet transcriptionally homogeneous. Furthermore, these three different TR1 specificities have similar diabetes reversal properties <jats:italic>in vivo<\/jats:italic> despite being uniquely reactive against the peptide MHCII-binding register displayed on the NPs. Thus, pMHCII-NP treatment using nanomedicines displaying different epitope specificities results in the simultaneous differentiation of multiple antigen-specific TFH-like cell clones into TR1-like cells that inherit the fine antigenic specificity of their precursors while acquiring a defined transcriptional immunoregulatory program.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1177722","type":"journal-article","created":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T05:18:50Z","timestamp":1681881530000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Transcriptional re-programming of insulin B-chain epitope-specific T-follicular helper cells into anti-diabetogenic T-regulatory type-1 cells"],"prefix":"10.3389","volume":"14","author":[{"given":"Patricia","family":"Sol\u00e9","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Parras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yamanouchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep","family":"Garnica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahir","family":"Garabatos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Moro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Monta\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debajyoti","family":"Mondal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9sar","family":"Fandos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pau","family":"Serra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pere","family":"Santamaria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nnano.2017.56","article-title":"Peptide-MHC-based nanomedicines for autoimmunity function as t-cell receptor microclustering devices","volume":"12","author":"Singha","year":"2017","journal-title":"Nat Nanotechnology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature16962","article-title":"Expanding antigen-specific regulatory networks to treat autoimmunity","volume":"530","author":"Clemente-Casares","year":"2016","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1038\/s41467-019-09893-5","article-title":"Suppression of a broad spectrum of liver autoimmune pathologies by single peptide-MHC-based nanomedicines","volume":"10","author":"Umeshappa","year":"2019","journal-title":"Nat Commun"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1172\/JCI130670","article-title":"Ubiquitous antigen-specific t regulatory type 1 cells variably suppress hepatic and extrahepatic autoimmunity","volume":"130","author":"Umeshappa","year":"2020","journal-title":"J Clin Invest"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-00989-z","article-title":"A t-follicular helper cell origin for t regulatory type-1 cells","author":"Sole","year":"2023","journal-title":"Press"},{"key":"B6","doi-asserted-by":"publisher","first-page":"108919","DOI":"10.1016\/j.celrep.2021.108919","article-title":"Liver-specific t-regulatory type-1 cells program local neutrophils to suppress hepatic autoimmunity via CRAMP","volume":"34","author":"Umeshappa","year":"2021","journal-title":"Cell Rep"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2012.10.024","article-title":"A novel pathway of presentation by class II-MHC molecules involving peptides or denatured proteins important in autoimmunity","volume":"55","author":"Mohan","year":"2013","journal-title":"Mol Immunol"},{"key":"B8","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 U. 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