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Ubiquitination is a mechanism that dictates surface MHC II with the attachment of a polyubiquitin chain to peptide-loaded MHC II, promoting its traffic away from the plasma membrane. In this study, we have examined how MHC II ubiquitination impacts the composition and function of both conventional CD4+ T cell and regulatory T cell (Treg) compartments. Responses were examined in two models of altered MHC II ubiquitination: MHCIIKRKI\/KI mice that express a mutant MHC II unable to be ubiquitinated or mice that lack membrane-associated RING-CH 8 (MARCH8), the E3 ubiquitin ligase responsible for MHC II ubiquitination specifically in thymic epithelial cells. Conventional CD4+ T cell populations in thymus, blood, and spleen of MHCIIKRKI\/KI and March8\u2212\/\u2212 mice were largely unaltered. In MLRs, March8\u2212\/\u2212, but not MHCIIKRKI\/KI, CD4+ T cells had reduced reactivity to both self\u2013 and allogeneic MHC II. Thymic Treg were significantly reduced in MHCIIKRKI\/KI mice, but not March8\u2212\/\u2212 mice, whereas splenic Treg were unaffected. Neither scenario provoked autoimmunity, with no evidence of immunohistopathology and normal levels of autoantibody. In summary, MHC II ubiquitination in specific APC types does not have a major impact on the conventional CD4+ T cell compartment but is important for Treg development.<\/jats:p>","DOI":"10.4049\/jimmunol.1901328","type":"journal-article","created":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T21:05:51Z","timestamp":1596488751000},"page":"1207-1216","source":"Crossref","is-referenced-by-count":15,"title":["Ubiquitination of MHC Class II Is Required for Development of Regulatory but Not Conventional CD4+ T Cells"],"prefix":"10.1093","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3103-6949","authenticated-orcid":false,"given":"Haiyin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute , Parkville, Victoria 3010 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Molecular Biology, The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute , Parkville, Victoria 3010 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0034-3527","authenticated-orcid":false,"given":"Annabelle B","family":"Blum","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute , Parkville, Victoria 3010 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Francis","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute , Parkville, Victoria 3010 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"Heinlein","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria 3052 ,","place":["Australia"]},{"name":"Department of Medical Biology, The University of Melbourne , Parkville, Victoria 3013 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Champa","family":"Nataraja","sequence":"additional","affiliation":[{"name":"Rheumatology Group, Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University , Clayton, Victoria 3168 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5634-9637","authenticated-orcid":false,"given":"James","family":"Harris","sequence":"additional","affiliation":[{"name":"Rheumatology Group, Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University , Clayton, Victoria 3168 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah A","family":"Jones","sequence":"additional","affiliation":[{"name":"Rheumatology Group, Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University , Clayton, Victoria 3168 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8457-8242","authenticated-orcid":false,"given":"Daniel H D","family":"Gray","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria 3052 ,","place":["Australia"]},{"name":"Department of Medical Biology, The University of Melbourne , Parkville, Victoria 3013 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