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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 2

Efficient isotype-dependent entry of s.c. administered antibodies into the draining LNs.

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Efficient isotype-dependent entry of s.c. administered antibodies into t...
(A and B) Flow cytometric analyses of the (A) dose dependency (fixed t = 5 min) and (B) time dependency (1-μg fixed dose) of B220-PB and CD4-FITC (both of the IgG subclass) entry into the draining LN after s.c administration. (C) Confocal analyses of the distribution of an unconjugated IgM antibody (MECA79) in the draining LN after s.c. administration (5 μg, t = 5 min, n = 4). Ex vivo stainings (serial sections) with MECA-79 show the total pool of positive cells. Scale bars: 20 μm. HEV, high endothelial venule. (D) Flow cytometric analyses of lymphocytes in the draining LN after s.c. administration of CD8 antibodies of IgG2a and IgM isotypes (2-μg dose, t = 30 min, n = 3). The cells were stained ex vivo for B220 and CD4. In the bar graphs, each dot represents 1 LN, and data are the mean ± SD. *P < 0.05 and ***P < 0.001, by Kruskal-Wallis (A and B) and Mann-Whitney U test (D).
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