{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T20:26:39Z","timestamp":1790022399916,"version":"4.0.1"},"reference-count":46,"publisher":"Rockefeller University Press","issue":"6","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI45073"],"award-info":[{"award-number":["AI45073"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5DP5OD012146"],"award-info":[{"award-number":["5DP5OD012146"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["105654\/Z\/14\/Z"],"award-info":[{"award-number":["105654\/Z\/14\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,5,30]]},"abstract":"<jats:p>Antibody affinity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation and selection. Selection involves B cells competing for T cell help based on the amount of antigen they capture and present on their MHC class II (MHCII) proteins. How GC B cells are able to rapidly and repeatedly transition between mutating their B cell receptor genes and then being selected shortly after is not known. We report that MHCII surface levels and degradation are dynamically regulated in GC B cells. Through ectopic expression of a photoconvertible MHCII-mKikGR chimeric gene, we found that individual GC B cells differed in the rates of MHCII protein turnover. Fluctuations in surface MHCII levels were dependent on ubiquitination and the E3 ligase March1. Increases in March1 expression in centroblasts correlated with decreases in surface MHCII levels, whereas CD83 expression in centrocytes helped to stabilize MHCII at that stage. Defects in MHCII ubiquitination caused GC B cells to accumulate greater amounts of a specific peptide\u2013MHCII (pMHCII), suggesting that MHCII turnover facilitates the replacement of old complexes. We propose that pMHCII complexes are periodically targeted for degradation in centroblasts to favor the presentation of recently acquired antigens, thereby promoting the fidelity and efficiency of selection.<\/jats:p>","DOI":"10.1084\/jem.20151682","type":"journal-article","created":{"date-parts":[[2016,5,9]],"date-time":"2016-05-09T10:12:30Z","timestamp":1462788750000},"page":"993-1009","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":84,"title":["Ubiquitin-mediated fluctuations in MHC class II facilitate efficient germinal center B cell responses"],"prefix":"10.1084","volume":"213","author":[{"given":"Oliver","family":"Bannard","sequence":"first","affiliation":[{"name":"Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, England, UK 1"},{"name":"Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143 5"},{"name":"Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon J.","family":"McGowan","sequence":"additional","affiliation":[{"name":"Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, England, UK 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonatan","family":"Ersching","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 02142 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Ishido","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Infection Immunity, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel D.","family":"Victora","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 02142 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeoung-Sook","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason G.","family":"Cyster","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143 5"},{"name":"Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 6"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,5,9]]},"reference":[{"key":"2023072603393040400_bib1","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1007\/978-1-61779-842-9_32","article-title":"IMGT\u00ae tools for the nucleotide analysis of immunoglobulin (IG) and T cell receptor (TR) V-(D)-J repertoires, polymorphisms, and IG mutations: IMGT\/V-QUEST and IMGT\/HighV-QUEST for NGS","volume":"882","author":"Alamyar","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"2023072603393040400_bib2","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1126\/science.1136736","article-title":"Imaging of germinal center selection events during affinity maturation","volume":"315","author":"Allen","year":"2007","journal-title":"Science."},{"key":"2023072603393040400_bib3","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1016\/j.immuni.2013.08.038","article-title":"Germinal center centroblasts transition to a centrocyte phenotype according to a timed program and depend on the dark zone for effective selection","volume":"39","author":"Bannard","year":"2013","journal-title":"Immunity."},{"key":"2023072603393040400_bib4","doi-asserted-by":"publisher","first-page":"2966","DOI":"10.4049\/jimmunol.1101643","article-title":"Ubiquitination of CD86 is a key mechanism in regulating antigen presentation by dendritic cells","volume":"187","author":"Baravalle","year":"2011","journal-title":"J. Immunol."},{"key":"2023072603393040400_bib5","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1093\/emboj\/19.4.513","article-title":"B cells extract and present immobilized antigen: implications for affinity discrimination","volume":"19","author":"Batista","year":"2000","journal-title":"EMBO J."},{"key":"2023072603393040400_bib6","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1038\/nature01004","article-title":"T-cell engagement of dendritic cells rapidly rearranges MHC class II transport","volume":"418","author":"Boes","year":"2002","journal-title":"Nature."},{"key":"2023072603393040400_bib7","doi-asserted-by":"publisher","first-page":"4959","DOI":"10.4049\/jimmunol.1102708","article-title":"Autoregulation of MARCH1 expression by dimerization and autoubiquitination","volume":"188","author":"Bourgeois-Daigneault","year":"2012","journal-title":"J. Immunol."},{"key":"2023072603393040400_bib8","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1038\/ni.2418","article-title":"The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers","volume":"13","author":"Calado","year":"2012","journal-title":"Nat. Immunol."},{"key":"2023072603393040400_bib9","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1038\/42030","article-title":"Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells","volume":"388","author":"Cella","year":"1997","journal-title":"Nature."},{"key":"2023072603393040400_bib10","doi-asserted-by":"publisher","first-page":"10449","DOI":"10.1073\/pnas.1507981112","article-title":"Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells","volume":"112","author":"Cho","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072603393040400_bib11","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1038\/nature01006","article-title":"Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane","volume":"418","author":"Chow","year":"2002","journal-title":"Nature."},{"key":"2023072603393040400_bib12","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/j.coi.2004.03.007","article-title":"B-cell antigen receptor signaling requirements for targeting antigen to the MHC class II presentation pathway","volume":"16","author":"Clark","year":"2004","journal-title":"Curr. Opin. Immunol."},{"key":"2023072603393040400_bib13","doi-asserted-by":"publisher","first-page":"3491","DOI":"10.1073\/pnas.0708874105","article-title":"MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation","volume":"105","author":"De Gassart","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072603393040400_bib14","doi-asserted-by":"publisher","first-page":"5961","DOI":"10.4049\/jimmunol.1300551","article-title":"Accelerated turnover of MHC class II molecules in nonobese diabetic mice is developmentally and environmentally regulated in vivo and dispensable for autoimmunity","volume":"190","author":"De Riva","year":"2013","journal-title":"J. Immunol."},{"key":"2023072603393040400_bib15","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1038\/ni.2428","article-title":"The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry","volume":"13","author":"Dominguez-Sola","year":"2012","journal-title":"Nat. Immunol."},{"key":"2023072603393040400_bib16","doi-asserted-by":"crossref","first-page":"3408","DOI":"10.4049\/jimmunol.162.6.3408","article-title":"Presentation of antigens internalized through the B cell receptor requires newly synthesized MHC class II molecules","volume":"162","author":"Forquet","year":"1999","journal-title":"J. Immunol."},{"key":"2023072603393040400_bib17","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1038\/nbt.1517","article-title":"Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells","volume":"27","author":"Foudi","year":"2009","journal-title":"Nat. Biotechnol."},{"key":"2023072603393040400_bib18","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1016\/S0092-8674(02)00673-6","article-title":"CD83 expression influences CD4+ T cell development in the thymus","volume":"108","author":"Fujimoto","year":"2002","journal-title":"Cell."},{"key":"2023072603393040400_bib19","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1038\/nature13300","article-title":"Clonal selection in the germinal centre by regulated proliferation and hypermutation","volume":"509","author":"Gitlin","year":"2014","journal-title":"Nature."},{"key":"2023072603393040400_bib20","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1126\/science.aac4919","article-title":"T cell help controls the speed of the cell cycle in germinal center B cells","volume":"349","author":"Gitlin","year":"2015","journal-title":"Science."},{"key":"2023072603393040400_bib21","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1084\/jem.20012059","article-title":"Germinal center B cells regulate their capability to present antigen by modulation of HLA-DO","volume":"195","author":"Glazier","year":"2002","journal-title":"J. Exp. Med."},{"key":"2023072603393040400_bib22","doi-asserted-by":"publisher","first-page":"e3944","DOI":"10.1371\/journal.pone.0003944","article-title":"mKikGR, a monomeric photoswitchable fluorescent protein","volume":"3","author":"Habuchi","year":"2008","journal-title":"PLoS One."},{"key":"2023072603393040400_bib23","doi-asserted-by":"publisher","first-page":"13789","DOI":"10.1073\/pnas.0605944103","article-title":"Testing gene function early in the B cell lineage in mb1-cre mice","volume":"103","author":"Hobeika","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072603393040400_bib24","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/S1074-7613(03)00175-4","article-title":"Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity","volume":"19","author":"Itano","year":"2003","journal-title":"Immunity."},{"key":"2023072603393040400_bib25","doi-asserted-by":"publisher","first-page":"6500","DOI":"10.4049\/jimmunol.0901521","article-title":"Discrete domains of MARCH1 mediate its localization, functional interactions, and posttranscriptional control of expression","volume":"183","author":"Jabbour","year":"2009","journal-title":"J. Immunol."},{"key":"2023072603393040400_bib26","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.immuni.2005.05.009","article-title":"The kinetic stability of MHC class II:peptide complexes is a key parameter that dictates immunodominance","volume":"23","author":"Lazarski","year":"2005","journal-title":"Immunity."},{"key":"2023072603393040400_bib27","doi-asserted-by":"publisher","first-page":"8820","DOI":"10.1073\/pnas.1202977109","article-title":"MHC class II distribution in dendritic cells and B cells is determined by ubiquitin chain length","volume":"109","author":"Ma","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072603393040400_bib28","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/1471-2105-13-31","article-title":"PANDAseq: paired-end assembler for illumina sequences","volume":"13","author":"Masella","year":"2012","journal-title":"BMC Bioinformatics."},{"key":"2023072603393040400_bib29","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1038\/sj.emboj.7601556","article-title":"Novel regulation of MHC class II function in B cells","volume":"26","author":"Matsuki","year":"2007","journal-title":"EMBO J."},{"key":"2023072603393040400_bib30","doi-asserted-by":"publisher","first-page":"e18817","DOI":"10.1371\/journal.pone.0018817","article-title":"Ubiquitin-dependent control of class II MHC localization is dispensable for antigen presentation and antibody production","volume":"6","author":"McGehee","year":"2011","journal-title":"PLoS One."},{"key":"2023072603393040400_bib31","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1038\/ni.3095","article-title":"Class-switched memory B cells remodel BCRs within secondary germinal centers","volume":"16","author":"McHeyzer-Williams","year":"2015","journal-title":"Nat. Immunol."},{"key":"2023072603393040400_bib32","doi-asserted-by":"publisher","first-page":"353","DOI":"10.2144\/05393ST03","article-title":"SAIVGeM: spreadsheet analysis of immunoglobulin VH gene mutations","volume":"39","author":"Messmer","year":"2005","journal-title":"Biotechniques."},{"key":"2023072603393040400_bib33","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1111\/imr.12303","article-title":"Molecular mechanism and cellular function of MHCII ubiquitination","volume":"266","author":"Oh","year":"2015","journal-title":"Immunol. Rev."},{"key":"2023072603393040400_bib34","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1084\/jem.20122695","article-title":"MARCH1-mediated MHCII ubiquitination promotes dendritic cell selection of natural regulatory T cells","volume":"210","author":"Oh","year":"2013","journal-title":"J. Exp. Med."},{"key":"2023072603393040400_bib35","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1007\/978-1-4939-2498-1_10","article-title":"Triggering positive selection of germinal center B cells by antigen targeting to DEC-205","volume":"1291","author":"Pasqual","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"2023072603393040400_bib36","doi-asserted-by":"publisher","first-page":"632","DOI":"10.4049\/jimmunol.167.2.632","article-title":"Cutting edge: editing of recycling class II:peptide complexes by HLA-DM","volume":"167","author":"Pathak","year":"2001","journal-title":"J. Immunol."},{"key":"2023072603393040400_bib37","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1038\/42039","article-title":"Developmental regulation of MHC class II transport in mouse dendritic cells","volume":"388","author":"Pierre","year":"1997","journal-title":"Nature."},{"key":"2023072603393040400_bib38","doi-asserted-by":"publisher","first-page":"5294","DOI":"10.4049\/jimmunol.1100406","article-title":"B cell-specific expression of B7-2 is required for follicular Th cell function in response to vaccinia virus","volume":"186","author":"Salek-Ardakani","year":"2011","journal-title":"J. Immunol."},{"key":"2023072603393040400_bib39","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1038\/nature05261","article-title":"Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination","volume":"444","author":"Shin","year":"2006","journal-title":"Nature."},{"key":"2023072603393040400_bib40","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1084\/jem.20092203","article-title":"CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10\u2013driven MARCH1-mediated ubiquitination and degradation","volume":"208","author":"Tze","year":"2011","journal-title":"J. Exp. Med."},{"key":"2023072603393040400_bib41","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.cell.2010.10.032","article-title":"Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter","volume":"143","author":"Victora","year":"2010","journal-title":"Cell."},{"key":"2023072603393040400_bib42","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1182\/blood-2012-03-415380","article-title":"Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas","volume":"120","author":"Victora","year":"2012","journal-title":"Blood."},{"key":"2023072603393040400_bib43","doi-asserted-by":"publisher","first-page":"4627","DOI":"10.4049\/jimmunol.164.9.4627","article-title":"Functional and phenotypic evidence for presentation of E\u03b152\u201368 structurally related self-peptide(s) in I-E\u03b1-deficient mice","volume":"164","author":"Viret","year":"2000","journal-title":"J. Immunol."},{"key":"2023072603393040400_bib44","doi-asserted-by":"publisher","first-page":"20465","DOI":"10.1073\/pnas.1010990107","article-title":"Ubiquitination regulates MHC class II-peptide complex retention and degradation in dendritic cells","volume":"107","author":"Walseng","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072603393040400_bib45","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.nbd.2007.10.004","article-title":"Restricted expression of mutant SOD1 in spinal motor neurons and interneurons induces motor neuron pathology","volume":"29","author":"Wang","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"2023072603393040400_bib46","doi-asserted-by":"publisher","first-page":"4601","DOI":"10.4049\/jimmunol.1400090","article-title":"Integrin-mediated interactions between B cells and follicular dendritic cells influence germinal center B cell fitness","volume":"192","author":"Wang","year":"2014","journal-title":"J. Immunol."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/213\/6\/993\/1756519\/jem_20151682.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/213\/6\/993\/1756519\/jem_20151682.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T23:44:19Z","timestamp":1690328659000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/213\/6\/993\/42073\/Ubiquitin-mediated-fluctuations-in-MHC-class-II"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5,9]]},"references-count":46,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2016,5,30]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20151682","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.726341872.793518621","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.726341872.793526099","asserted-by":"object"}]},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,9]]}}}