{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T06:05:15Z","timestamp":1780380315950,"version":"3.54.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006502","name":"Defense Sciences Office, DARPA","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006502","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Adaptive immune activation in lymph nodes requires rare antigen-specific na\u00efve T cells to locate antigen-bearing dendritic cells within a spatially structured stromal network. Reduced priming efficiency is typically attributed to weak T cell receptor signaling, yet it remains unclear whether failure arises from impaired signaling or from limited access to antigen-bearing dendritic cells during early scanning.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed COORDINATE, a spatially explicit agent-based model of lymph node microanatomy that integrates fibroblastic reticular cell topology, chemokine-guided migration, and competition for dendritic cell access.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We show that stromal architecture and trafficking biases strongly influence which T cells encounter antigen, while competition for limited dendritic cell access can exclude a substantial fraction of cells from forming any productive contact. Consequently, reduced activation can arise from failed clonal recruitment rather than diminished signaling following contact.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These results support a view of early T cell priming as an access-limited process and indicate that commonly used endpoint measurements can conflate failure to access antigen with failure to activate. Together, our findings suggest that improving early antigen access, rather than strengthening signaling alone, may represent an alternative strategy to enhance adaptive immune responses.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1843390","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:42:17Z","timestamp":1780378937000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial topology and competitive access differentially shape early T cell priming in the lymph node: an agent-based modeling approach"],"prefix":"10.3389","volume":"17","author":[{"given":"Laia","family":"Vancells","sequence":"first","affiliation":[{"name":"Weldon School of Biomedical Engineering, Purdue University","place":["West Lafayette, IN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leopold","family":"Green","sequence":"additional","affiliation":[{"name":"Weldon School of Biomedical Engineering, Purdue University","place":["West Lafayette, IN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Kong","sequence":"additional","affiliation":[{"name":"Weldon School of Biomedical Engineering, Purdue University","place":["West Lafayette, IN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3298","article-title":"HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes","volume":"12","author":"Girard","year":"2012","journal-title":"Nat Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2588","article-title":"Stromal cell contributions to the homeostasis and functionality of the immune system","volume":"9","author":"Mueller","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1016\/j.immuni.2006.10.011","article-title":"Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes","volume":"25","author":"Baj\u00e9noff","year":"2006","journal-title":"Immunity"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nature02238","article-title":"T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases","volume":"427","author":"Mempel","year":"2004","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20061706","article-title":"CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo","volume":"204","author":"Worbs","year":"2007","journal-title":"J Exp Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2012.02.007","article-title":"Lymph node homing of T cells and dendritic cells via afferent lymphatics","volume":"33","author":"F\u00f6rster","year":"2012","journal-title":"Trends Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1146\/annurev.immunol.021908.132706","article-title":"T cell activation","volume":"27","author":"Smith-Garvin","year":"2009","journal-title":"Annu Rev Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2010.02.013","article-title":"Inflammatory cytokines as a third signal for T cell activation","volume":"22","author":"Curtsinger","year":"2010","journal-title":"Curr Opin Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260044","article-title":"Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion","volume":"346","author":"Marchingo","year":"2014","journal-title":"Science"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0030356","article-title":"Modeling T cell antigen discrimination based on feedback control of digital ERK responses","volume":"3","author":"Altan-Bonnet","year":"2005","journal-title":"PloS Biol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1126\/science.1158013","article-title":"Variability and robustness in T cell activation from regulated heterogeneity in protein levels","volume":"321","author":"Feinerman","year":"2008","journal-title":"Science"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041236","article-title":"Imaging the single cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes","volume":"200","author":"Miller","year":"2004","journal-title":"J Exp Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/0471142956.cy1226s60","article-title":"Two\u2010photon imaging of the immune system","volume":"60","author":"Dzhagalov","year":"2012","journal-title":"CP Cytometry"},{"key":"B14","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-3-540-71029-5_2","article-title":"Dendritic cell migration to peripheral lymph nodes","volume-title":"Dendritic Cells","author":"Mart\u00edn-Fontecha","year":"2009"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2021.11.007","article-title":"Intravital and high-content multiplex imaging of the immune system","volume":"32","author":"Hor","year":"2022","journal-title":"Trends Cell Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nri2638","article-title":"Analysing immune cell migration","volume":"9","author":"Beltman","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1183286","article-title":"New tools for immunologists: models of lymph node function from cells to tissues","volume":"14","author":"Ozulumba","year":"2023","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics16050666","article-title":"Lymph node-on-chip technology: Cutting-edge advances in immune microenvironment simulation","volume":"16","author":"Wang","year":"2024","journal-title":"Pharmaceutics"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02428","article-title":"Integrative computational modeling of the lymph node stromal cell landscape","volume":"9","author":"Novkovic","year":"2018","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903117","article-title":"Characterizing the dynamics of CD4+ T cell priming within a lymph node","volume":"184","author":"Linderman","year":"2010","journal-title":"J Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2009.78","article-title":"Agent\u2010based simulation of T\u2010cell activation and proliferation within a lymph node","volume":"88","author":"Bogle","year":"2010","journal-title":"Immunol Cell Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-101721-040924","article-title":"Modeling T cell fate","volume":"41","author":"De Boer","year":"2023","journal-title":"Annu Rev Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1548768","article-title":"Multi-physiology modeling of the immune system in the era of precision immunotherapy","volume":"16","author":"Hong","year":"2025","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2011.06.037","article-title":"Systems biology approaches for understanding cellular mechanisms of immunity in lymph nodes during infection","volume":"287","author":"Mirsky","year":"2011","journal-title":"J Theor Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s11538-016-0214-9","article-title":"Mathematical models for immunology: Current state of the art and future research directions","volume":"78","author":"Eftimie","year":"2016","journal-title":"Bull Math Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2008.60","article-title":"Simulating T\u2010cell motility in the lymph node paracortex with a packed lattice geometry","volume":"86","author":"Bogle","year":"2008","journal-title":"Immunol Cell Biol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.jtbi.2011.11.001","article-title":"T-cell movement on the reticular network","volume":"295","author":"Donovan","year":"2012","journal-title":"J Theor Biol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002436","article-title":"Influence of the fibroblastic reticular network on cell-cell interactions in lymphoid organs","volume":"8","author":"Graw","year":"2012","journal-title":"PloS Comput Biol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1002515","article-title":"Topological small-world organization of the fibroblastic reticular cell network determines lymph node functionality","volume":"14","author":"Novkovic","year":"2016","journal-title":"PloS Biol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/j.celrep.2019.12.070","article-title":"Topological structure and robustness of the lymph node conduit system","volume":"30","author":"Novkovic","year":"2020","journal-title":"Cell Rep"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.aca.2017.11.048","article-title":"Diffusion of cytokines in live lymph node tissue using microfluidic integrated optical imaging","volume":"1000","author":"Ross","year":"2018","journal-title":"Anal Chim Acta"},{"key":"B32","article-title":"Pharmacokinetics of recombinant interleukin 2 in humans","volume":"50","author":"Konrad","year":"1990","journal-title":"Cancer Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2004.08.005","article-title":"Dynamic behavior of T cells and thymocytes in lymphoid organs as revealed by two-photon microscopy","volume":"21","author":"Bousso","year":"2004","journal-title":"Immunity"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/nri1845","article-title":"Dendritic cells in a mature age","volume":"6","author":"Reis E Sousa","year":"2006","journal-title":"Nat Rev Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402520","article-title":"Fibroblastic reticular cells: organization and regulation of the T lymphocyte life cycle","volume":"194","author":"Brown","year":"2015","journal-title":"J Immunol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1111\/imr.12758","article-title":"Compartmentalization of dendritic cell and T-cell interactions in the lymph node: Anatomy of T-cell fate decisions","volume":"289","author":"Le\u00f3n","year":"2019","journal-title":"Immunol Rev"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1126\/science.1071065","article-title":"Dynamic imaging of T cell-dendritic cell interactions in lymph nodes","volume":"296","author":"Stoll","year":"2002","journal-title":"Science"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2008.00588.x","article-title":"Decoding the dynamics of T cell\u2013dendritic cell interactions in vivo","volume":"221","author":"Celli","year":"2008","journal-title":"Immunol Rev"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.45","article-title":"Agent\u2010based models in translational systems biology","volume":"1","author":"An","year":"2009","journal-title":"WIREs Mech Dis"},{"key":"B40","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/s41577-018-0088-1","article-title":"Dendritic cell subsets in T cell programming: location dictates function","volume":"19","author":"Eisenbarth","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.241828","article-title":"The lymph node at a glance - how spatial organization optimizes the immune response","volume":"133","author":"Grant","year":"2020","journal-title":"J Cell Sci"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abg0336","article-title":"Effective CD4 T cell priming requires repertoire scanning by CD301b+ migratory cDC2 cells upon lymph node entry","volume":"6","author":"Tatsumi","year":"2021","journal-title":"Sci Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2021.06.006","article-title":"Lymph node fibroblastic reticular cells steer immune responses","volume":"42","author":"Li","year":"2021","journal-title":"Trends Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxh113","article-title":"A novel reticular stromal structure in lymph node cortex: an immuno-platform for interactions among dendritic cells, T cells and B cells","volume":"16","author":"Katakai","year":"2004","journal-title":"Int Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12945","article-title":"Conversations that count: Cellular interactions that drive T cell fate","volume":"300","author":"Duckworth","year":"2021","journal-title":"Immunol Rev"},{"key":"B46","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.coi.2019.02.002","article-title":"Studying interactions between dendritic cells and T cells in vivo","volume":"58","author":"Chudnovskiy","year":"2019","journal-title":"Curr Opin Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20200795","article-title":"Lymph node fibroblastic reticular cells regulate differentiation and function of CD4 T cells via CD25","volume":"219","author":"Kim","year":"2022","journal-title":"J Exp Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.10.5165","article-title":"CD8 T cell clonal expansion and development of effector function require prolonged exposure to antigen, costimulation, and signal 3 cytokine","volume":"171","author":"Curtsinger","year":"2003","journal-title":"J Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00563","article-title":"The timing of T cell priming and cycling","volume":"6","author":"Obst","year":"2015","journal-title":"Front Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1126\/science.1221063","article-title":"A decade of imaging cellular motility and interaction dynamics in the immune system","volume":"336","author":"Germain","year":"2012","journal-title":"Science"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1126\/science.1070051","article-title":"Two-photon imaging of lymphocyte motility and antigen response in intact lymph node","volume":"296","author":"Miller","year":"2002","journal-title":"Science"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1843390\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:42:18Z","timestamp":1780378938000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1843390\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,2]]},"references-count":51,"alternative-id":["10.3389\/fimmu.2026.1843390"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1843390","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,2]]},"article-number":"1843390"}}