A novel computational model predicts key regulators of chemokine gradient formation in lymph nodes and site-specific roles for CCL19 and ACKR4

Jafarnejad, M., Zawieja, D. C., Brook, B. S., Nibbs, R. J.B. and Moore, Jr., J. E. (2017) A novel computational model predicts key regulators of chemokine gradient formation in lymph nodes and site-specific roles for CCL19 and ACKR4. Journal of Immunology, 199(7), pp. 2291-2304. (doi: 10.4049/jimmunol.1700377) (PMID:28807994) (PMCID:PMC5602158)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nibbs, Professor Rob
Authors: Jafarnejad, M., Zawieja, D. C., Brook, B. S., Nibbs, R. J.B., and Moore, Jr., J. E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Immunology
Publisher:American Association of Immunologists
ISSN:0022-1767
ISSN (Online):1550-6606
Published Online:14 August 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Journal of Immunology 199(7):2291-2304
Publisher Policy:Reproduced under a Creative Commons license

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