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

Jafarnejad, Mohammad; Zawieja, David C.; Brook, Bindi S.; Nibbs, Robert J.B.; Moore, James E.

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. Here, 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.

Citation

Jafarnejad, M., Zawieja, D. C., Brook, B. S., Nibbs, R. J., & Moore, 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), 2291-2304. https://doi.org/10.4049/jimmunol.1700377

• Journal Article Type: Article
• Acceptance Date: Jul 11, 2017
• Online Publication Date: Aug 14, 2017
• Publication Date: Oct 1, 2017
• Deposit Date: Jul 14, 2017
• Publicly Available Date: Aug 14, 2017
• Journal: Journal of Immunology
• Print ISSN: 0022-1767
• Electronic ISSN: 1550-6606
• Publisher: American Association of Immunologists
• Peer Reviewed: Peer Reviewed
• Volume: 199
• Issue: 7
• Pages: 2291-2304
• DOI: https://doi.org/10.4049/jimmunol.1700377
• Keywords: lymph flow, leukocyte migration, sub capsular sinus
• Public URL: https://nottingham-repository.worktribe.com/output/877637
• Publisher URL: http://www.jimmunol.org/content/199/7/2291
• Contract Date: Jul 14, 2017