{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:58:10Z","timestamp":1792000690623,"version":"4.4.0"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["VI.Vidi.192.084"],"award-info":[{"award-number":["VI.Vidi.192.084"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TR-SFB654 project C4"],"award-info":[{"award-number":["TR-SFB654 project C4"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>The adaptive immune system recognizes billions of unique antigens using highly variable T cell receptors (TCRs). To what extent TCR features shape the spatial distribution of the TCR repertoire (TCR-R) within lymphoid organs remains unclear. Here, we compared the TCR-R composition in T cell zones (TCZ), B cell zones (BCZ), and germinal centers (GC) of the spleen by analyzing the complementarity-determining region 3 of the beta chain (CDR3\u03b2) in microdissected splenic compartments from na\u00efve and immunized mice. While we found substantial differences in TCR-R composition between these compartments, these differences largely disappeared once the effects of compartment size and proliferation were accounted for: During steady state, the few T cells found in BCZs strongly resemble random subsets of those found in TCZs. After immunization, expanded clones started appearing in the TCZ at day 3 and later shifted to the BCZ. GCs harbored even further expanded clones that were grouped into clusters with high sequence similarity. TCR-R differences during the immune response were well explained by a Galton-Watson model of T cell proliferation, suggesting that this could be the central factor shaping the observed TCR-R differences. Similarly, while TCR length and closeness to germline initially showed more pronounced differences between the compartments, our models of random distribution and proliferation explained these differences almost entirely. Hence, our findings suggest that splenic TCR-Rs are shaped predominantly by compartment size and proliferation rates rather than TCR sequence features. This would imply that quantitative assessment of TCR-R dynamics across heterogeneous spatial compartments during an immune response is only possible when these effects are explicitly accounted for.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1014859","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:43:27Z","timestamp":1791999807000},"page":"e1014859","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["How compartmentalization and proliferation shape the splenic T cell repertoire during an immune response to a complex antigen in mice"],"prefix":"10.1371","volume":"22","author":[{"given":"Franka","family":"Buytenhuijs","sequence":"first","affiliation":[{"name":"Radboud University","place":["Nijmegen, The Netherlands"],"department":["Data Science Group, Institute for Computing and Information Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia","family":"Tune","sequence":"additional","affiliation":[{"name":"Universit\u00e4t zu L\u00fcbeck","place":["L\u00fcbeck, Germany"],"department":["Institut f\u00fcr Anatomie"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas C.","family":"Smits","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center","place":["Nijmegen, The Netherlands"],"department":["Medical BioSciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Schampel","sequence":"additional","affiliation":[{"name":"Universit\u00e4t zu L\u00fcbeck","place":["L\u00fcbeck, Germany"],"department":["Institut f\u00fcr Anatomie"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa-Kristin","family":"Schierloh","sequence":"additional","affiliation":[{"name":"Universit\u00e4t zu L\u00fcbeck","place":["L\u00fcbeck, Germany"],"department":["Institut f\u00fcr Anatomie"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"Pagel","sequence":"additional","affiliation":[{"name":"Universit\u00e4t zu L\u00fcbeck","place":["L\u00fcbeck, Germany"],"department":["Institut f\u00fcr Anatomie"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Westermann","sequence":"additional","affiliation":[{"name":"Universit\u00e4t zu L\u00fcbeck","place":["L\u00fcbeck, Germany"],"department":["Institut f\u00fcr Anatomie"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0459-9458","authenticated-orcid":true,"given":"Johannes","family":"Textor","sequence":"additional","affiliation":[{"name":"Radboud University","place":["Nijmegen, The Netherlands"],"department":["Data Science Group, Institute for Computing and Information Sciences"]},{"name":"Radboud University Medical Center","place":["Nijmegen, The Netherlands"],"department":["Medical BioSciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,14]]},"reference":[{"issue":"6181","key":"pcbi.1014859.ref001","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/334395a0","article-title":"T-cell antigen receptor genes and T-cell recognition","volume":"334","author":"MM Davis","year":"1988","journal-title":"Nature"},{"key":"pcbi.1014859.ref002","doi-asserted-by":"crossref","first-page":"485","DOI":"10.3389\/fimmu.2013.00485","article-title":"Estimating the diversity, completeness, and cross-reactivity of the T cell repertoire","volume":"4","author":"VI Zarnitsyna","year":"2013","journal-title":"Front Immunol"},{"key":"pcbi.1014859.ref003","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.jtbi.2015.10.016","article-title":"How many TCR clonotypes does a body maintain?","volume":"389","author":"G Lythe","year":"2016","journal-title":"Journal of Theoretical Biology"},{"issue":"2","key":"pcbi.1014859.ref004","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/s41577-023-00911-8","article-title":"A guide to thymic selection of T cells","volume":"24","author":"KM Ashby","year":"2024","journal-title":"Nat Rev Immunol"},{"issue":"12","key":"pcbi.1014859.ref005","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/nri2669","article-title":"Antigen presentation in the thymus for positive selection and central tolerance induction","volume":"9","author":"L Klein","year":"2009","journal-title":"Nat Rev Immunol"},{"issue":"4","key":"pcbi.1014859.ref006","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nri2941","article-title":"Recombination centres and the orchestration of V(D)J recombination","volume":"11","author":"DG Schatz","year":"2011","journal-title":"Nat Rev Immunol"},{"issue":"7","key":"pcbi.1014859.ref007","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/BF00184787","article-title":"Distribution of lymphocyte subsets and natural killer cells in the human body","volume":"70","author":"J Westermann","year":"1992","journal-title":"Clin Investig"},{"issue":"33","key":"pcbi.1014859.ref008","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.aau6085","article-title":"Structure and function of the immune system in the spleen","volume":"4","author":"SM Lewis","year":"2019","journal-title":"Sci Immunol"},{"issue":"7850","key":"pcbi.1014859.ref009","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/s41586-021-03187-x","article-title":"Dynamic regulation of TFH selection during the germinal centre reaction","volume":"591","author":"J Merkenschlager","year":"2021","journal-title":"Nature"},{"issue":"2","key":"pcbi.1014859.ref010","article-title":"Clonal composition and persistence of antigen-specific circulating T follicular helper cells","volume":"53","author":"M Hu","year":"2023","journal-title":"Eur J Immunol"},{"issue":"6146","key":"pcbi.1014859.ref011","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1126\/science.1241680","article-title":"T follicular helper cell dynamics in germinal centers","volume":"341","author":"Z Shulman","year":"2013","journal-title":"Science"},{"issue":"2","key":"pcbi.1014859.ref012","article-title":"Primary germinal center-resident T follicular helper cells are a physiologically distinct subset of CXCR5hiPD-1hi T follicular helper cells","volume":"55","author":"C-H Yeh","year":"2022","journal-title":"Immunity"},{"issue":"11","key":"pcbi.1014859.ref013","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/nri1714","article-title":"Follicular B helper T cells in antibody responses and autoimmunity","volume":"5","author":"CG Vinuesa","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"pcbi.1014859.ref014","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1146\/annurev-immunol-020711-075032","article-title":"Germinal centers","volume":"30","author":"GD Victora","year":"2012","journal-title":"Annu Rev Immunol"},{"key":"pcbi.1014859.ref015","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.molimm.2021.08.009","article-title":"Mapping the spatial distribution of T cells in repertoire dimension","volume":"138","author":"J Zhang","year":"2021","journal-title":"Mol Immunol"},{"issue":"6","key":"pcbi.1014859.ref016","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0067746","article-title":"Dose-dependent induction of murine Th1\/Th2 responses to sheep red blood cells occurs in two steps: antigen presentation during second encounter is decisive","volume":"8","author":"C Stamm","year":"2013","journal-title":"PLoS One"},{"key":"pcbi.1014859.ref017","doi-asserted-by":"crossref","first-page":"100082","DOI":"10.1016\/j.bbih.2020.100082","article-title":"Effects of sleep on the splenic milieu in mice and the T cell receptor repertoire recruited into a T cell dependent B cell response","volume":"5","author":"C Tune","year":"2020","journal-title":"Brain Behav Immun Health"},{"key":"pcbi.1014859.ref018","doi-asserted-by":"crossref","first-page":"100312","DOI":"10.1016\/j.bbih.2021.100312","article-title":"Sleep restriction prior to antigen exposure does not alter the T cell receptor repertoire but impairs germinal center formation during a T cell-dependent B cell response in murine spleen","volume":"16","author":"C Tune","year":"2021","journal-title":"Brain Behav Immun Health"},{"issue":"2","key":"pcbi.1014859.ref019","doi-asserted-by":"crossref","first-page":"350","DOI":"10.4049\/jimmunol.1800091","article-title":"Deep Sequencing Reveals Transient Segregation of T Cell Repertoires in Splenic T Cell Zones during an Immune Response","volume":"201","author":"J Textor","year":"2018","journal-title":"J Immunol"},{"issue":"7","key":"pcbi.1014859.ref020","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"CA Schneider","year":"2012","journal-title":"Nat Methods"},{"issue":"1","key":"pcbi.1014859.ref021","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1186\/s12859-017-1575-2","article-title":"ClonoCalc and ClonoPlot: immune repertoire analysis from raw files to publication figures with graphical user interface","volume":"18","author":"A F\u00e4hnrich","year":"2017","journal-title":"BMC Bioinformatics"},{"issue":"17","key":"pcbi.1014859.ref022","doi-asserted-by":"crossref","first-page":"2974","DOI":"10.1093\/bioinformatics\/btz035","article-title":"OLGA: fast computation of generation probabilities of B- and T-cell receptor amino acid sequences and motifs","volume":"35","author":"Z Sethna","year":"2019","journal-title":"Bioinformatics"},{"issue":"2","key":"pcbi.1014859.ref023","first-page":"129","article-title":"Multi-type Galton-Watson process as a model for proliferating human tumour cell populations derived from stem cells: estimation of stem cell self-renewal probabilities in human ovarian carcinomas","volume":"19","author":"A Ciampi","year":"1986","journal-title":"Cell Tissue Kinet"},{"key":"pcbi.1014859.ref024","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2021"},{"key":"pcbi.1014859.ref025","volume-title":"Analysis of T cell receptor repertoires from T- and B cell zones in the murine spleen","author":"F Buytenhuijs","year":"2026"},{"issue":"8","key":"pcbi.1014859.ref026","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0273264","article-title":"The splenic T cell receptor repertoire during an immune response against a complex antigen: Expanding private clones accumulate in the high and low copy number region","volume":"17","author":"M Meinhardt","year":"2022","journal-title":"PLoS One"},{"issue":"11","key":"pcbi.1014859.ref027","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/0167-5699(92)90070-N","article-title":"The evolution of immune memory and germinal centers","volume":"13","author":"MH Nahm","year":"1992","journal-title":"Immunol Today"},{"issue":"1","key":"pcbi.1014859.ref028","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1002\/eji.201343811","article-title":"Activated CD4+ T cells enter the splenic T-cell zone and induce autoantibody-producing germinal centers through bystander activation","volume":"44","author":"D Banczyk","year":"2014","journal-title":"Eur J Immunol"},{"issue":"7661","key":"pcbi.1014859.ref029","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/nature22976","article-title":"Identifying specificity groups in the T cell receptor repertoire","volume":"547","author":"J Glanville","year":"2017","journal-title":"Nature"},{"issue":"7661","key":"pcbi.1014859.ref030","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nature22383","article-title":"Quantifiable predictive features define epitope-specific T cell receptor repertoires","volume":"547","author":"P Dash","year":"2017","journal-title":"Nature"},{"issue":"1","key":"pcbi.1014859.ref031","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/imr.12665","article-title":"Predicting the spectrum of TCR repertoire sharing with a data-driven model of recombination","volume":"284","author":"Y Elhanati","year":"2018","journal-title":"Immunol Rev"},{"issue":"1","key":"pcbi.1014859.ref032","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1111\/imr.12031","article-title":"T-cell subsets in the germinal center","volume":"252","author":"RR Ramiscal","year":"2013","journal-title":"Immunol Rev"},{"key":"pcbi.1014859.ref033","volume-title":"Pattern and process in a forested ecosystem: disturbance, development and the steady state based on the Hubbard Brook ecosystem study","author":"FH Bormann","year":"2012"},{"key":"pcbi.1014859.ref034","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.22057","article-title":"T cell receptor repertoires of mice and humans are clustered in similarity networks around conserved public CDR3 sequences","volume":"6","author":"A Madi","year":"2017","journal-title":"Elife"},{"issue":"3","key":"pcbi.1014859.ref035","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/BF00534904","article-title":"Limit theorems for the Galton-Watson process with time-dependent immigration","volume":"20","author":"JH Foster","year":"1971","journal-title":"Z Wahrscheinlichkeitstheorie verw Gebiete"},{"key":"pcbi.1014859.ref036","doi-asserted-by":"crossref","unstructured":"Boianelli A, Pettini E, Prota G, Medaglini D, Vicino A. Identification of a branching process model for adaptive immune response. In: 52nd IEEE Conference on Decision and Control, 2013. 7205\u201310. https:\/\/doi.org\/10.1109\/cdc.2013.6761032","DOI":"10.1109\/CDC.2013.6761032"},{"issue":"2","key":"pcbi.1014859.ref037","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1038\/icb.2009.78","article-title":"Agent-based simulation of T-cell activation and proliferation within a lymph node","volume":"88","author":"G Bogle","year":"2010","journal-title":"Immunol Cell Biol"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1014859","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:43:44Z","timestamp":1791999824000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1014859"}},"subtitle":[],"editor":[{"given":"Philipp Martin","family":"Altrock","sequence":"first","affiliation":[{"name":"Kiel University","place":["GERMANY"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,10,14]]},"references-count":37,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,10,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1014859","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,14]]}}}