{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T08:44:25Z","timestamp":1768553065018,"version":"3.49.0"},"posted":{"date-parts":[[2022,2,6]]},"group-title":"Allergy and Immunology","reference-count":14,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2022,2,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  T-cell development is a major physiological process occurring in complex organisms, that ensures the formation of T-cell receptors diverse repertoire, to recognize antigens throughout the life of the organism. The thymus offers a microenvironment for efficient development, where progenitor populations go through maturation steps, which, when not regulated, are associated with disease onset, including autoimmune disorders and cancer. Glycosylation is a major post-translational modification that occurs in virtually all cells, including T lymphocytes, regulating receptor- turnover, affinity and signaling. However, there is a missing knowledge on how glycans regulate lymphocyte development and their impact in T-cell functions. We discovered stage-specific glycosylation profiles in human and murine thymocyte populations. Thereafter, we generated two glycoengineered mouse models displaying\n                  <jats:italic>N<\/jats:italic>\n                  -glycosylation pathway deficiencies, at early DN stages, lacking the\n                  <jats:italic>Mgat1<\/jats:italic>\n                  or\n                  <jats:italic>Mgat2<\/jats:italic>\n                  genes. We demonstrated remarkable defects in key T-cell developmental stages, such as \u00df- and DP-selection, natural regulatory T-cell generation,\n                  <jats:italic>\u03b3\u03b4<\/jats:italic>\n                  T development\/differentiation and thymic egression, in\n                  <jats:italic>Mgat1<\/jats:italic>\n                  -deficient thymocytes, indicating a pathogenic role of mannose\n                  <jats:italic>N<\/jats:italic>\n                  -glycans in development. We also demonstrated that a single\n                  <jats:italic>N<\/jats:italic>\n                  - glycan antenna (modelled in\n                  <jats:italic>Mgat2<\/jats:italic>\n                  -deficient thymocytes) is sufficient to rescue key developmental processes. In conclusion, we demonstrated that mannosylated thymocytes render a dysregulation in T-cell development, associated with disease.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"22270265v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2022.02.04.22270265","type":"posted-content","created":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T01:30:15Z","timestamp":1644197415000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>N<\/i>\n                  -glycans mannosylation controls T-cell development by reprogramming thymocyte commitment, fate and repertoire"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2961-0801","authenticated-orcid":false,"given":"Manuel M","family":"Vicente","sequence":"first","affiliation":[]},{"given":"In\u00eas","family":"Alves","sequence":"additional","affiliation":[]},{"given":"\u00c2ngela","family":"Fernandes","sequence":"additional","affiliation":[]},{"given":"Ana M","family":"Dias","sequence":"additional","affiliation":[]},{"given":"Elena","family":"P\u00e9rez-Anton","sequence":"additional","affiliation":[]},{"given":"Alexandra","family":"Correia","sequence":"additional","affiliation":[]},{"given":"Afonso R M","family":"Almeida","sequence":"additional","affiliation":[]},{"given":"Gabriel A","family":"Rabinovich","sequence":"additional","affiliation":[]},{"given":"Manuel","family":"Vilanova","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4618-9799","authenticated-orcid":false,"given":"Ana E","family":"Sousa","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3484-5162","authenticated-orcid":false,"given":"Salom\u00e9 S","family":"Pinho","sequence":"additional","affiliation":[]}],"member":"54368","reference":[{"key":"2022020901201044000_2022.02.04.22270265v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-092910-154008"},{"key":"2022020901201044000_2022.02.04.22270265v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2017.07.010"},{"key":"2022020901201044000_2022.02.04.22270265v1.3","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20032183"},{"key":"2022020901201044000_2022.02.04.22270265v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3422"},{"key":"2022020901201044000_2022.02.04.22270265v1.5","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.21.120601.141107"},{"key":"2022020901201044000_2022.02.04.22270265v1.6","first-page":"7842","article-title":"Glycans as Key Checkpoints of T-cell Activity and Function","volume":"9","year":"2019","journal-title":"Frontiers in Immunology"},{"key":"2022020901201044000_2022.02.04.22270265v1.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1720409115"},{"key":"2022020901201044000_2022.02.04.22270265v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3982"},{"key":"2022020901201044000_2022.02.04.22270265v1.9","unstructured":"Varki A , Cummings RD , Esko JD , Stanley P , Hart GW , Aebi M , et al. Essentials of Glycobiology. 3rd ed. Cold Spring Harbor (NY); 2015."},{"key":"2022020901201044000_2022.02.04.22270265v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/ni1482"},{"key":"2022020901201044000_2022.02.04.22270265v1.11","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.4049\/jimmunol.177.4.2431","article-title":"Activation of Murine CD4+ and CD8+ T Lymphocytes Leads to Dramatic Remodeling of N-Linked Glycans","volume":"177","year":"2006","journal-title":"The Journal of Immunology"},{"key":"2022020901201044000_2022.02.04.22270265v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00577-3"},{"key":"2022020901201044000_2022.02.04.22270265v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3007"},{"issue":"9","key":"2022020901201044000_2022.02.04.22270265v1.14","first-page":"2416","article-title":"Dysregulation of T-cell receptor N-glycosylation: a molecular mechanism involved in ulcerative colitis","volume":"23","year":"2013","journal-title":"Human Molecular Genetics"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2022.02.04.22270265","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T14:35:52Z","timestamp":1768487752000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2022.02.04.22270265"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,6]]},"references-count":14,"URL":"https:\/\/doi.org\/10.1101\/2022.02.04.22270265","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s41423-023-01052-7","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2022,2,6]]},"subtype":"preprint"}}