The Biophysics of Lymphatic Transport: Engineering Tools and Immunological Consequences

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Abstract

Lymphatic vessels mediate fluid flows that affect antigen distribution and delivery, lymph node stromal remodeling, and cell-cell interactions, to thus regulate immune activation. Here we review the functional role of lymphatic transport and lymph node biomechanics in immunity. We present experimental tools that enable quantitative analysis of lymphatic transport and lymph node dynamics in vitro and in vivo. Finally, we discuss the current understanding for how changes in lymphatic transport and lymph node biomechanics contribute to pathogenesis of conditions including cancer, aging, neurodegeneration, and infection.

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Lymphology; Biophysics; Biomechanics; Biological Sciences Tools

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Most cited references 130

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The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node.

Michael Sixt, Nobuo Kanazawa, Manuel Selg … (2005)

Resident dendritic cells (DC) within the T cell area of the lymph node take up soluble antigens that enter via the afferent lymphatics before antigen carrying DC arrive from the periphery. The reticular network within the lymph node is a conduit system forming the infrastructure for the fast delivery of soluble substances from the afferent lymph to the lumen of high endothelial venules (HEVs). Using high-resolution light microscopy and 3D reconstruction, we show here that these conduits are unique basement membrane-like structures ensheathed by fibroblastic reticular cells with occasional resident DC embedded within this cell layer. Conduit-associated DC are capable of taking up and processing soluble antigens transported within the conduits, whereas immigrated mature DC occur remote from the reticular fibers. The conduit system is, therefore, not a closed compartment that shuttles substances through the lymph node but represents the morphological equivalent to the filtering function of the lymph node.

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Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming.

Rhys S. Allan, Jason Waithman, Sammy Bedoui … (2006)

Skin dendritic cells (DCs) are thought to act as key initiators of local T cell immunity. Here we show that after skin infection with herpes simplex virus (HSV), cytotoxic T lymphocyte (CTL) activation required MHC class I-restricted presentation by nonmigratory CD8(+) DCs rather than skin-derived DCs. Despite a lack of direct presentation by migratory DCs, blocking their egress from infected skin substantially inhibited class I-restricted presentation and HSV-specific CTL responses. These results support the argument for initial transport of antigen by migrating DCs, followed by its transfer to the lymphoid-resident DCs for presentation and CTL priming. Given that relatively robust CTL responses were seen with small numbers of skin-emigrant DCs, we propose that this inter-DC antigen transfer functions to amplify presentation across a larger network of lymphoid-resident DCs for efficient T cell activation.

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Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks

Deepali Malhotra, Anne Fletcher, Jillian L. Astarita … (2012)

Lymph node stromal cells (LNSCs) closely regulate immunity and self-tolerance, yet key aspects of their biology remain poorly illuminated. Comparative transcriptomic analyses of murine LNSC subsets revealed expression of important immune mediators, growth factors, and novel structural components. Pairwise analyses of ligands and cognate receptors across hematopoietic and stromal subsets suggested a complex web of cross-talk. Compared with skin and thymic fibroblasts, fibroblastic reticular cells (FRCs) were enriched in genes relevant to cytokine signaling. LNSCs from inflamed lymph nodes upregulated acute phase response genes, chemokines, and antigen presentation genes. Poorly studied podoplanin−CD31− LNSCs showed similarities to FRCs, but lacked IL-7 expression, and were identified as myofibroblastic integrin α7+ pericytes. Together these data comprehensively describe the transcriptional characteristics of LNSC subsets.

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Author and article information

Contributors

Amanda W. Lund

Susan N. Thomas

Journal

Journal ID (nlm-ta): iScience

Journal ID (iso-abbrev): iScience

Title: iScience

Publisher: Elsevier

ISSN (Electronic): 2589-0042

Publication date PMC-release: 06 November 2019

Publication date Collection: 20 December 2019

Publication date (Electronic): 06 November 2019

Volume: 22

Pages: 28-43

Affiliations

[1 ]Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive NW, Atlanta, GA 30332, USA

[2 ]Departments of Cell Developmental Cancer Biology, Molecular Microbiology & Immunology, and Dermatology, Knight Cancer Institute, Oregon Health & Science University, 2720 SW Moody Avenue, KR-CDCB, Portland, OR 97239, USA

[3 ]Parker H. Petit Institute for Bioengineering and Bioscience, 315 Ferst Dr NW, Georgia Institute of Technology, Atlanta, GA 30332, USA

[4 ]George W. Woodruff School of Mechanical Engineering, 801 Ferst Dr NW, Georgia Institute of Technology, Atlanta, GA 30332, USA

[5 ]Winship Cancer Institute, 1365 Clifton Rd, Emory University, Atlanta, GA 30322, USA

Author notes

[∗ ]Corresponding author lunda@ 123456ohsu.edu

[∗∗ ]Corresponding author susan.thomas@ 123456gatech.edu

Article

Publisher ID: S2589-0042(19)30455-9

DOI: 10.1016/j.isci.2019.11.005

PMC ID: 6864335

PubMed ID: 31739172

SO-VID: f1908e55-7823-468d-94f9-ab58b00727f2

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The Biophysics of Lymphatic Transport: Engineering Tools and Immunological Consequences

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Most cited references 130

The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node.

Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming.

Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks

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