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Transcytosis route mediates rapid delivery of intact antibodies to draining lymph nodes
Laura Kähäri, … , Johanna Ivaska, Marko Salmi
Laura Kähäri, … , Johanna Ivaska, Marko Salmi
Published June 24, 2019
Citation Information: J Clin Invest. 2019;129(8):3086-3102. https://doi.org/10.1172/JCI125740.
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Research Article Immunology Vascular biology

Transcytosis route mediates rapid delivery of intact antibodies to draining lymph nodes

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Abstract

Lymph nodes (LNs) filter lymph to mount effective immune responses. Small soluble lymph-borne molecules from the periphery enter the draining LNs via a reticular conduit system. Intact antibodies and other larger molecules, in contrast, are physically unable to enter the conduits, and they are thought to be transported to the LNs only within migratory DCs after proteolytic degradation. Here, we discovered that lymph-borne antibodies and other large biomolecules enter within seconds into the parenchyma of the draining LN in an intact form. Mechanistically, we found that the uptake of large molecules is a receptor-independent, fluid-phase process that takes place by dynamin-dependent vesicular transcytosis through the lymphatic endothelial cells in the subcapsular sinus of the LN. Physiologically, this pathway mediates a very fast transfer of large protein antigens from the periphery to LN-resident DCs and macrophages. We show that exploitation of the transcytosis system allows enhanced whole-organ imaging and spatially controlled lymphocyte activation by s.c. administered antibodies in vivo. Transcytosis through the floor of the subcapsular sinus thus represents what we believe to be a new physiological and targetable mode of lymph filtering.

Authors

Laura Kähäri, Ruth Fair-Mäkelä, Kaisa Auvinen, Pia Rantakari, Sirpa Jalkanen, Johanna Ivaska, Marko Salmi

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Figure 11

Antibody transcytosis allows efficient whole-mount imaging and spatially controlled lymphocyte activation in the draining LNs.

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Antibody transcytosis allows efficient whole-mount imaging and spatially...
(A) Whole-mount imaging of an optically cleared draining LN after s.c. injection of the indicated fluorochrome-conjugated antibodies (10 μg each, t = 30 min, n = 4). Scale bar: 50 μm. (B) Flow cytometric analyses of lymphocyte activation in draining LNs (dLNs) and nondraining LNs (Non-dLNs) after s.c. administration of anti-CD3 and anti–TCR-β antibodies (2 μg each, t = 18 h, n = 3). The cells were stained ex vivo for CD69, CD25, CD4, and CD8. (C and D) Representative CFSE dilution histograms of CD45.2+ OTII donor cells (C) and quantification (D) of OTII lymphocyte proliferation (undivided CFSEhi cells) in the draining and nondraining popliteal LNs after s.c. administration of OVA and control (IgG), agonistic (clone D665), and function-blocking (clone 37.51) CD28 antibodies (n = 3). LPS was used as a positive control. (E–G) The agonistic and function-blocking CD28 antibodies were administered separately to the 2 different legs of the same animal (the same experimental setup as in C), and OTII activation (E and F) and total numbers (G) in the draining LN were measured (n = 5). In the bar graphs, each dot represents 1 LN, and data are the mean ± SD. *P < 0.05 and **P < 0.01, by Mann-Whitney U test (B, F, and G) and Kruskal-Wallis followed by Dunn’s test (D). Ctrl, control.
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