title: Ubiquitin-mediated fluctuations in MHC class II facilitate efficient germinal center B cell responses.
abstract: 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-MHCII (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.
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, England, UK Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143 Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 oliver.bannard@ndm.ox.ac.uk jason.cyster@ucsf.edu.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bannard
authors.affiliation: Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, England, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: McGowan
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Ersching
authors.affiliation: Laboratory of Integrative Infection Immunity, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishido
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Gabriel D
authors.initials: GD
authors.lastname: Victora
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Jeoung-Sook
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143 Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 oliver.bannard@ndm.ox.ac.uk jason.cyster@ucsf.edu.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology; D018858:Germinal Center / Q000276:immunology* / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D059748:Proteolysis; D025801:Ubiquitin / Q000235:genetics / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology*; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000097802:CD83 Antigen; C545340:MARCH1 protein, mouse