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CCR7-dependent navigation is determined by the distribution of extracellular CCL19 and CCL21, which form concentration gradients at specific microanatomical locations. The mechanisms underpinning the establishment and regulation of these gradients are poorly understood. In this article, we have incorporated multiple biochemical processes describing the CCL19\u2013CCL21\u2013CCR7\u2013ACKR4 network into our model of LN fluid flow to establish a computational model to investigate intranodal chemokine gradients. Importantly, the model recapitulates CCL21 gradients observed experimentally in B cell follicles and interfollicular regions, building confidence in its ability to accurately predict intranodal chemokine distribution. Parameter variation analysis indicates that the directionality of these gradients is robust, but their magnitude is sensitive to these key parameters: chemokine production, diffusivity, matrix binding site availability, and CCR7 abundance. The model indicates that lymph flow shapes intranodal CCL21 gradients, and that CCL19 is functionally important at the boundary between B cell follicles and the T cell area. It also predicts that ACKR4 in LNs prevents CCL19\/CCL21 accumulation in efferent lymph, but does not control intranodal gradients. Instead, it attributes the disrupted interfollicular CCL21 gradients observed in Ackr4-deficient LNs to ACKR4 loss upstream. Our novel approach has therefore generated new testable hypotheses and alternative interpretations of experimental data. Moreover, it acts as a framework to investigate gradients at other locations, including those that cannot be visualized experimentally or involve other chemokines.<\/jats:p>","DOI":"10.4049\/jimmunol.1700377","type":"journal-article","created":{"date-parts":[[2017,8,15]],"date-time":"2017-08-15T00:30:20Z","timestamp":1502757020000},"page":"2291-2304","source":"Crossref","is-referenced-by-count":34,"title":["A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4"],"prefix":"10.1093","volume":"199","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1550-0011","authenticated-orcid":false,"given":"Mohammad","family":"Jafarnejad","sequence":"first","affiliation":[{"name":"Department of Bioengineering, Imperial College London , London SW7 2AZ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2644-6524","authenticated-orcid":false,"given":"David C","family":"Zawieja","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Texas A&M Health Science Center , Temple, TX 76504"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bindi S","family":"Brook","sequence":"additional","affiliation":[{"name":"School of Mathematical Sciences, University of Nottingham , Nottingham NG7 2RD,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8150-0044","authenticated-orcid":false,"given":"Robert J B","family":"Nibbs","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8TA,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1604-158X","authenticated-orcid":false,"suffix":"Jr.","given":"James E","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Imperial College London , London SW7 2AZ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,10,1]]},"reference":[{"key":"2025030614472101500_r1","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1146\/annurev-immunol-032713-120145","article-title":"Chemokines and chemokine receptors: positioning cells for host defense and immunity","volume":"32","author":"Griffith","year":"2014","journal-title":"Annu. 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