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FcRn-mediated antibody transport across epithelial cells revealed by electron tomography

He, Wanzhong and Ladinsky, Mark S. and Huey-Tubman, Kathryn E. and Jensen, Grant J. and McIntosh, J. Richard and Bjorkman, Pamela J. (2008) FcRn-mediated antibody transport across epithelial cells revealed by electron tomography. Nature, 455 (7212). pp. 542-546. ISSN 0028-0836. PMCID PMC2773227. doi:10.1038/nature07255.

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The neonatal Fc receptor (FcRn) transports maternal IgG across epithelial barriers, thereby providing the fetus or newborn with humoral immunity before its immune system is fully functional. In newborn rats, FcRn transfers IgG from milk to blood by apical-to-basolateral transcytosis across intestinal epithelial cells. The pH difference between the apical (pH 6.0–6.5) and basolateral (pH 7.4) sides of intestinal epithelial cells facilitates the efficient unidirectional transport of IgG, because FcRn binds IgG at pH 6.0–6.5 but not at pH 7 or more. As milk passes through the neonatal intestine, maternal IgG is removed by FcRn-expressing cells in the proximal small intestine (duodenum and jejunum); remaining proteins are absorbed and degraded by FcRn-negative cells in the distal small intestine (ileum). Here we use electron tomography to make jejunal transcytosis visible directly in space and time, developing new labelling and detection methods to map individual nanogold-labelled Fc within transport vesicles and simultaneously to characterize these vesicles by immunolabelling. Combining electron tomography with a nonperturbing endocytic label allowed us to conclusively identify receptor-bound ligands, resolve interconnecting vesicles, determine whether a vesicle was microtubule-associated, and accurately trace FcRn-mediated transport of IgG. Our results present a complex picture in which Fc moves through networks of entangled tubular and irregular vesicles, only some of which are microtubule-associated, as it migrates to the basolateral surface. New features of transcytosis are elucidated, including transport involving multivesicular body inner vesicles/tubules and exocytosis through clathrin-coated pits. Markers for early, late and recycling endosomes each labelled vesicles in different and overlapping morphological classes, revealing spatial complexity in endo-lysosomal trafficking.

Item Type:Article
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URLURL TypeDescription CentralArticle ReadCube access
Ladinsky, Mark S.0000-0002-1036-3513
Huey-Tubman, Kathryn E.0000-0002-4683-8138
Jensen, Grant J.0000-0003-1556-4864
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2008 Nature Publishing Group. We thank D. Mastronarde for advice about setting up SerialEM on the Caltech microscopes and three-dimensional modelling; C. Kivork for preparing Au-Fc and Au-dextran; B. Tivol for assistance with electron microscopes; M. Murphy for help with schematic figures; M. Morphew for contributions to silver enhancement methods; Y. Nie, A. Feuerabendt, A. Kules, C. Luna, K. McKenzie, R. Sander and L. Zinn-Bjorkman for segmenting tomograms; J. Vielmetter for SPR studies of Au-Fc; and F. Brodsky, F. Maxfield, S. Schmid and D. Tesar for discussions. This work was supported by the National Institutes of Health (2 R37 AI041239-06A1 to P.J.B. and RR000592 to J.R.M.), a Max Planck Research Award (P.J.B.), gifts from the Gordon and Betty Moore Foundation and the Agouron Institute to support electron microscopy at Caltech, and National University of Singapore AcRF start-up funds (R-154-000-339-133 to W.H.). Author Contributions: W.H. and P.J.B. conceived the experiments. Electron microscopy data were collected by W.H. in collaboration with and in the microscopy laboratory established by G.J.J. at Caltech. W.H. configured SerialEM on the Caltech electron microscopes, prepared intestinal samples by chemical fixation or HPF/FSF, conceived and developed the gold enhancement procedures, and collected, processed, interpreted and modelled tomograms. W.H. and K.E.H.T conducted kinetic experiments. Immunolabelling and associated imaging was done by M.S.L. in Boulder with enhanced samples provided by W.H. and K.E.H.T. Initial phases of the project using transfected cells were conducted by P.J.B. in Boulder in collaboration with J.R.M. and the Boulder Laboratory for 3D Microscopy of Cells. All authors discussed and interpreted the results and edited the manuscript.
Funding AgencyGrant Number
NIH2 R37 AI041239-06A1
Max Planck SocietyUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
Agouron InstituteUNSPECIFIED
National University of SingaporeR-154-000-339-133
Issue or Number:7212
PubMed Central ID:PMC2773227
Record Number:CaltechAUTHORS:HEWnat08
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13276
Deposited On:05 Feb 2009 05:22
Last Modified:08 Nov 2021 22:36

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