{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T12:46:09Z","timestamp":1780058769287,"version":"3.54.0"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T00:00:00Z","timestamp":1617062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Human B-cell differentiation has been extensively investigated on genomic and transcriptomic grounds; however, no studies have accomplished so far detailed analysis of antigen-dependent maturation-associated human B-cell populations from a proteomic perspective. Here, we investigate for the first time the quantitative proteomic profiles of B-cells undergoing antigen-dependent maturation using a label-free LC-MS\/MS approach applied on 5 purified B-cell subpopulations (naive, centroblasts, centrocytes, memory and plasma B-cells) from human tonsils (data are available <jats:italic>via<\/jats:italic> ProteomeXchange with identifier PXD006191). Our results revealed that the actual differences among these B-cell subpopulations are a combination of expression of a few maturation stage-specific proteins within each B-cell subset and maturation-associated changes in relative protein expression levels, which are related with metabolic regulation. The considerable overlap of the proteome of the 5 studied B-cell subsets strengthens the key role of the regulation of the stoichiometry of molecules associated with metabolic regulation and programming, among other signaling cascades (such as antigen recognition and presentation and cell survival) crucial for the transition between each B-cell maturation stage.<\/jats:p>","DOI":"10.3389\/fimmu.2021.637832","type":"journal-article","created":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T14:20:00Z","timestamp":1617114000000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Dynamic Intracellular Metabolic Cell Signaling Profiles During Ag-Dependent B-Cell Differentiation"],"prefix":"10.3389","volume":"12","author":[{"given":"Paula","family":"D\u00edez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mart\u00edn","family":"P\u00e9rez-Andr\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"B\u00f8gsted","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikel","family":"Azkargorta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Garc\u00eda-Valiente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa M.","family":"D\u00e9gano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila","family":"Mateos-Gomez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma","family":"B\u00e1rcena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Santa Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"G\u00f3ngora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F\u00e9lix","family":"Elortza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Landeira-Vi\u00f1uela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Juanes-Velasco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Segura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ra\u00fal","family":"Manzano-Rom\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Almeida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Dybkaer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Orfao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Fuentes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2014.59","article-title":"Human memory B cells isolated from blood and tonsils are functionally distinctive","volume":"92","author":"P\u00e9rez","year":"2014","journal-title":"Immunol Cell Biol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.immuni.2007.07.009","article-title":"Germinal-Center Organization and Cellular Dynamics","volume":"27","author":"Allen","year":"2007","journal-title":"Immunity"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1309\/AJCPDQNP2U5DZHVV","article-title":"Multiparametric flow cytometry for identification and fluorescence activated cell sorting of five distinct B-cell subpopulations in normal tonsil tissue","volume":"136","author":"Kjeldsen","year":"2011","journal-title":"Am J Clin Pathol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nri3804","article-title":"Dynamics of B cells in germinal centres","volume":"15","author":"De Silva","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3460","article-title":"Regulated selection of germinal-center cells into the memory B cell compartment","volume":"17","author":"Shinnakasu","year":"2016","journal-title":"Nat Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/ni1172","article-title":"STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression","volume":"6","author":"Scheeren","year":"2005","journal-title":"Nat Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.3.475","article-title":"bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells","volume":"191","author":"Smith","year":"2000","journal-title":"J Exp Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3291","article-title":"Whole-genome fingerprint of the DNA methylome during human\u00a0B cell differentiation","volume":"47","author":"Kulis","year":"2015","journal-title":"Nat Genet"},{"key":"B9","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1038\/nri1633","article-title":"Transcriptional networks in developing and mature B cells","volume":"5","author":"Matthias","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.01.025","article-title":"Hematopoiesis: An Evolving Paradigm for Stem Cell Biology","volume":"132","author":"Orkin","year":"2008","journal-title":"Cell"},{"key":"B11","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.cell.2011.01.004","article-title":"Densely interconnected transcriptional circuits control cell states in human hematopoiesis","volume":"144","author":"Novershtern","year":"2011","journal-title":"Cell"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nature10113","article-title":"Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia","volume":"475","author":"Puente","year":"2011","journal-title":"Nature"},{"key":"B13","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1111\/imr.12046","article-title":"Regulation of B-cell development and function by microRNAs","volume":"253","author":"de Y\u00e9benes","year":"2013","journal-title":"Immunol Rev"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0115911","article-title":"The transcriptomic and proteomic landscapes of bone marrow and secondary lymphoid tissues","volume":"9","author":"Andersson","year":"2014","journal-title":"PloS One"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0138236","article-title":"Long noncoding RNA expression during human B-cell development","volume":"10","author":"Petri","year":"2015","journal-title":"PloS One"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e77894","DOI":"10.1371\/journal.pone.0077894","article-title":"Proteomic Changes during B Cell Maturation: 2D-DIGE Approach","volume":"8","author":"Salonen","year":"2013","journal-title":"PloS One"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.200600156","article-title":"Proteome analysis of B-cell maturation","volume":"6","author":"Salonen","year":"2006","journal-title":"Proteomics"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M500123-MCP200","article-title":"Expression clustering reveals detailed co-expression patterns of functionally related proteins during B cell differentiation: a proteomic study using a combination of one-dimensional gel electrophoresis, LC-MS\/MS, and stable isotope labeling by amino acid","volume":"4","author":"Romijn","year":"2005","journal-title":"Mol Cell Proteomics"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1021\/pr200328f","article-title":"Metabolomics of B to plasma cell differentiation","volume":"10","author":"Garcia-Manteiga","year":"2011","journal-title":"J Proteome Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/1477-5956-7-43","article-title":"A comparison between protein profiles of B cell subpopulations and mantle cell lymphoma cells","volume":"7","author":"Stranneheim","year":"2009","journal-title":"Proteome Sci"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.01.029","article-title":"The Coming Age of Complete, Accurate, and Ubiquitous Proteomes","volume":"49","author":"Mann","year":"2013","journal-title":"Mol Cell"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-01-197368.The","article-title":"Increased frequency (12 %) of circulating chronic lymphocytic leukemia \u2013 like B-cell clones in healthy subjects using a highly sensitive multicolor flow cytometry approach","volume":"114","author":"Nieto","year":"2009","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.468","article-title":"In-gel digestion for mass spectrometric characterization of proteins and proteomes","volume":"1","author":"Shevchenko","year":"2007","journal-title":"Nat Protoc"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.261","article-title":"Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips","volume":"2","author":"Rappsilber","year":"2007","journal-title":"Nat Protoc"},{"key":"B25","volume-title":"R: A Language and Environment for Statistical Computing","year":"2011"},{"key":"B26","doi-asserted-by":"publisher","article-title":"RStudio: Integrated Development for R","year":"2016","DOI":"10.1007\/978-81-322-2340-5"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"B28","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1186\/1471-2105-14-244","article-title":"RCircos: an R package for Circos 2D track plots","volume":"14","author":"Zhang","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1109\/TVCG.2014.2346248","article-title":"{UpSet}: Visualization of Intersecting Sets","volume":"20","author":"Lex","year":"2014","journal-title":"IEEE Trans Vis Comput Graph ({InfoVis} \u201814)"},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.1109\/ICMIC.2016.7804123","article-title":"Density-based spatial clustering of application with noise algorithm for the classification of solar radiation time series","author":"Khalil","year":"2016"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bti525","article-title":"BioMart and Bioconductor: A powerful link between biological databases and microarray data analysis","volume":"21","author":"Durinck","year":"2005","journal-title":"Bioinformatics"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.97","article-title":"Mapping identifiers for the integration of genomic datasets with the R\/Bioconductor package biomaRt","volume":"4","author":"Durinck","year":"2009","journal-title":"Nat Protoc"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1101\/gr.130062.111","article-title":"Chimeras taking shape: potential functions of proteins encoded by chimeric RNA transcripts","volume":"22","author":"Frenkel-Morgenstern","year":"2012","journal-title":"Genome Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/484271a","article-title":"Proteomics: The interaction map","volume":"484","author":"Baker","year":"2012","journal-title":"Nature"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.5b00474[doi","article-title":"Integration of Proteomics and Transcriptomics Data Sets for the Analysis of a Lymphoma B-Cell Line in the Context of the Chromosome-Centric Human Proteome Project","volume":"14","author":"Diez","year":"2015","journal-title":"J\u00a0Proteome Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3185","article-title":"Insights into the regulation of protein abundance from proteomic and transcriptomic analyses","volume":"13","author":"Vogel","year":"2012","journal-title":"Nat Rev Genet"},{"key":"B37","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/nrg3356","article-title":"Next-generation proteomics: towards an integrative view of proteome dynamics","volume":"14","author":"Altelaar","year":"2013","journal-title":"Nat Rev Genet"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.07.032","article-title":"Is Proteomics the New Genomics","volume":"130","author":"Cox","year":"2007","journal-title":"Cell"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0060139","article-title":"Rgs13 Constrains Early B Cell Responses and Limits Germinal Center Sizes","volume":"8","author":"Hwang","year":"2013","journal-title":"PloS One"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.12.8620","article-title":"Vav proteins regulate the plasma cell program and secretory Ig production","volume":"177","author":"Stephenson","year":"2006","journal-title":"J Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.coi.2017.03.006","article-title":"Plasma cell and memory B cell differentiation from the germinal center","volume":"45","author":"Suan","year":"2017","journal-title":"Curr Opin Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/ni1357","article-title":"Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination","volume":"7","author":"Klein","year":"2006","journal-title":"Nat Immunol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"40133","DOI":"10.1038\/srep40133","article-title":"Tyrosine kinase c-Abl regulates the survival of plasma cells","volume":"7","author":"Li","year":"2017","journal-title":"Sci Rep"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-02-078071","article-title":"B lymphocytes: How they develop and function","volume":"112","author":"Lebien","year":"2008","journal-title":"Blood"},{"key":"B45","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1016\/j.ajhg.2012.04.015","article-title":"Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity","volume":"90","author":"Lopez-Herrera","year":"2012","journal-title":"Am J Hum Genet"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402708","article-title":"Circulating Human CD27-IgA+ Memory B Cells Recognize Bacteria with Polyreactive Igs","volume":"195","author":"Berkowska","year":"2015","journal-title":"J Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400943","article-title":"Themis2 Is Not Required for B Cell Development, Activation, and Antibody Responses","volume":"193","author":"Hartweger","year":"2014","journal-title":"J Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxg037","article-title":"Human germinal center B cells differ from naive and memory B cells by their aggregated MHC class II-rich compartments lacking HLA-DO","volume":"15","author":"Chalouni","year":"2003","journal-title":"Int Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602353103","article-title":"Tracking germinal center B cells expressing germ-line immunoglobulin gamma1 transcripts by conditional gene targeting","volume":"103","author":"Casola","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1884","article-title":"14-3-3 adaptor proteins recruit AID to 5\u2032-AGCT-3\u2032\u2013rich switch regions for class switch recombination","volume":"17","author":"Xu","year":"2010","journal-title":"Nat Struct Mol Biol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V110.11.692.692","article-title":"CARD11 as an Oncogene in Diffuse Large B Cell Lymphoma","volume":"110","author":"Lenz","year":"2015","journal-title":"Blood"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1053\/j.semdp.2011.04.001","article-title":"Molecular pathogenesis of diffuse large B-cell lymphoma","volume":"28","author":"Schneider","year":"2011","journal-title":"Semin Diagn Pathol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.4161\/cc.11.5.19300","article-title":"The role of TRADD in death receptor signaling","volume":"11","author":"Pobezinskaya","year":"2012","journal-title":"Cell Cycle"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/ni976","article-title":"Caspase-3 regulates cell cycle in B cells: a consequence of substrate specificity","volume":"4","author":"Woo","year":"2003","journal-title":"Nat Immunol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1084\/jem.185.3.563","article-title":"Germinal center founder cells display propensity for apoptosis before onset of somatic mutation","volume":"185","author":"Lebecque","year":"1997","journal-title":"J Exp Med"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.152327399","article-title":"Molecular portraits of B cell lineage commitment","volume":"99","author":"M\u00fcschen","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1007\/s11302-014-9427-2","article-title":"Purinergic signalling and immune cells","volume":"10","author":"Burnstock","year":"2014","journal-title":"Purinergic Signal"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E16-10-0722","article-title":"Vamp-7-dependent secretion at the immune synapse regulates antigen extraction and presentation in B-lymphocytes","volume":"28","author":"Obino","year":"2017","journal-title":"Mol Biol Cell"},{"key":"B59","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18388\/abp.2017_1588","article-title":"Purinergic signaling in B cells","volume":"65","author":"Przybyla","year":"2018","journal-title":"Acta Biochim Pol"},{"key":"B60","doi-asserted-by":"publisher","first-page":"194","DOI":"10.5114\/ceji.2018.77390","article-title":"Immunological memory cells","volume":"43","author":"Ratajczak","year":"2018","journal-title":"Cent Eur J Immunol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0244-2","article-title":"B cell memory: building two walls of protection against pathogens","volume":"20","author":"Akkaya","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-03-208256","article-title":"High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia","volume":"114","author":"Herling","year":"2009","journal-title":"Blood"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2010.02.018","article-title":"Clinical consequences of defects in B-cell development","volume":"125","author":"Vale","year":"2010","journal-title":"J Allergy Clin Immunol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2016.105","article-title":"Functional disparities among BCL-2 members in tonsillar and leukemic B-cell subsets assessed by BH3-mimetic profiling","volume":"24","author":"Peperzak","year":"2017","journal-title":"Cell Death Differ"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1145","article-title":"update of the PRIDE database and its related tools","volume":"44","author":"Vizca\u00edno","year":"2016","journal-title":"Nucleic Acids Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.637832\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T14:20:11Z","timestamp":1617114011000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.637832\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,30]]},"references-count":65,"alternative-id":["10.3389\/fimmu.2021.637832"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.637832","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,30]]},"article-number":"637832"}}