A novel computational model predicts key regulators of chemokine gradient formation in lymph nodes and site-specific roles for CCL19 and ACKR4
File(s)
Published version
OA Location
Author(s)
Jafarnejad, M
Zawieja, DC
Brook, BS
Nibbs, RJB
Moore Jr, JE
Type
Journal Article
Abstract
The chemokine receptor CCR7 drives leukocyte migration into and within lymph nodes (LNs). It is activated by chemokines CCL19 and CCL21, which are scavenged by the atypical chemokine receptor ACKR4. 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-CCL21-CCR7-ACKR4 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.
Date Issued
2017-10-01
Date Acceptance
2017-07-11
Citation
Journal of Immunology, 2017, 199 (7), pp.2291-2304
ISSN
0022-1767
Publisher
American Association of Immunologists
Start Page
2291
End Page
2304
Journal / Book Title
Journal of Immunology
Volume
199
Issue
7
Copyright Statement
Copyright © 2017 The Authors
This article is distributed under the terms of the CC BY 4.0 Unported license.
This article is distributed under the terms of the CC BY 4.0 Unported license.
License URL
Identifier
PII: jimmunol.1700377
Subjects
Animals
B-Lymphocytes
Cell Movement
Chemokine CCL19
Computer Simulation
Dendritic Cells
Humans
Lymph Nodes
Mice
Receptors, CCR
Receptors, CCR7
T-Lymphocytes
Lymph Nodes
B-Lymphocytes
Dendritic Cells
T-Lymphocytes
Animals
Humans
Mice
Cell Movement
Computer Simulation
Receptors, CCR
Receptors, CCR7
Chemokine CCL19
1107 Immunology
Immunology
Publication Status
Published online
Date Publish Online
2017-09-18