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Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis

Ladinsky, Mark S. and Araujo, Leandro P. and Zhang, Xiao and Veltri, John and Galan-Diez, Marta and Soualhi, Salima and Lee, Carolyn and Irie, Koichiro and Pinker, Elisha Y. and Narushima, Seiko and Bandyopadhyay, Sheila and Nagayama, Manabu and Elhenawy, Wael and Coombes, Brian K. and Ferraris, Ronaldo P. and Honda, Kenya and Iliev, Iliyan D. and Gao, Nan and Bjorkman, Pamela J. and Ivanov, Ivaylo I. (2019) Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis. Science, 363 (6431). Art. No. eaat4042. ISSN 0036-8075. PMCID PMC6708280. https://resolver.caltech.edu/CaltechAUTHORS:20190307-133956667

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[img] Video (QuickTime) (Movie S1. Tomographic reconstruction of a SFB synapse with an IEC. Numerous cargo-containing MATE vesicles are forming from the invaginated IEC plasma membrane at the holdfast tip) - Supplemental Material
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[img] Video (QuickTime) (Movie S2. Detail of a cargo-containing MATE vesicle at the tip of a SFB holdfast. The MATE vesicle is forming from the invaginated IEC plasma membrane) - Supplemental Material
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Abstract

Commensal bacteria influence host physiology, without invading host tissues. We show that proteins from segmented filamentous bacteria (SFB) are transferred into intestinal epithelial cells (IECs) through adhesion-directed endocytosis that is distinct from the clathrin-dependent endocytosis of invasive pathogens. This process transfers microbial cell wall–associated proteins, including an antigen that stimulates mucosal T helper 17 (T_H17) cell differentiation, into the cytosol of IECs in a cell division control protein 42 homolog (CDC42)–dependent manner. Removal of CDC42 activity in vivo led to disruption of endocytosis induced by SFB and decreased epithelial antigen acquisition, with consequent loss of mucosal T_H17 cells. Our findings demonstrate direct communication between a resident gut microbe and the host and show that under physiological conditions, IECs acquire antigens from commensal bacteria for generation of T cell responses to the resident microbiota.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1126/science.aat4042DOIArticle
https://www.sciencemag.org/content/363/6431/eaat4042/suppl/DC1PublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708280PubMed CentralArticle
ORCID:
AuthorORCID
Ladinsky, Mark S.0000-0002-1036-3513
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://www.sciencemag.org/about/science-licenses-journal-article-reuse. This is an article distributed under the terms of the Science Journals Default License. Received for publication February 22, 2018. Resubmitted October 11, 2018. Accepted for publication January 28, 2019. We thank D. Littman (NYU) for generously providing 7B8 Tg mice and anti-P3340 antibody. We thank Y. Zheng (Cincinnati Children’s Hospital) for providing CDC42-flox mice. We thank C. Jobin (University of Florida) for providing AIEC strain LF82. We thank E. Byington from the JP Sulzberger Columbia Genome Center for help with RNA-seq analysis. We thank members of the Ivanov and Gao laboratories for technical help. We thank S. Ghosh and S. Reiner for providing advice and feedback throughout the project and for help with the manuscript. We thank E. Reeder from LNinnovations and M. Murphy for assistance with illustrations. This work was supported by funding from the following sources: NIH R21 AI126305 and R01 DK098378 (I.I.I.); P50 GM082545 (P.J.B); NIH R01 DK102934 and ACS Research Scholar Award 15-060-01-TBE (N.G.); NSF/BIO/IOS 1456673 (R.P.F.); NIH R01 AT010243 (N.G. and R.P.F.); AMED-LEAP JP17 g0010003 and Takeda Science Foundation (K.H.); CIHR Grant 324932 (B.K.C.); Columbia University Schaefer Research Award (I.I.I.); and Pew Charitable Trust Innovation Fund Award 00031379 (I.I.I and P.J.B.). Author contributions: P.J.B and I.I.I. conceived and supervised the study. M.S.L., L.P.A. and I.I.I. designed the study, experiments, and wrote the manuscript. M.S.L. performed all electron tomography and electron microscopy experiments. L.P.A. performed in vivo experiments and analyzed the data. X.Z., J.V., M.G.-D., S.S., C.L., K.I., E.Y.P., S.N., S.B., W.E., B.K.C., R.P.F., K.H., I.D.I., and N.G. participated in performing experiments, provided intellectual expertise, and helped to interpret experimental results. X.Z. and N.G. performed CDC42 activation assays and confocal microscopy experiments and analysis. J.V. performed externalized intestinal loops experiments. M.G.-D., L.P.A., and K.I. performed analysis of intestinal immune subsets in IEC^(ΔCDC42) and IEC^(ΔCDC42-CKO) mice and analyzed the data. S.S. performed confocal microscopy experiments and analysis. C.L. prepared samples for RNA-seq and performed RT-PCR experiments. E.Y.P. analyzed electron tomography data. S.N. and K.H. performed gnotobiotic experiments. M.N. isolated and provided B. adolescentis. W.E. and B.K.C. performed colonization experiments with AIEC strain NRG857c. I.D.I. helped with analysis of RNA-seq data and prepared corresponding figures. Competing interests: K.H. is a scientific advisory board member at Vedanta Biosciences. Data and materials availability: The accession number for the RNA-seq datasets is NCBI BioProject GSE124848. All other data needed to evaluate the conclusions in this paper are present either in the main text or the supplementary materials.
Funders:
Funding AgencyGrant Number
NIHR21 AI126305
NIHR01 DK098378
NIHP50 GM082545
NIHR01 DK102934
American Cancer Society15-060-01-TBE
NSFIOS-1456673
NIHR01 AT010243
Japan Agency for Medical Research and DevelopmentJP17 g0010003
Takeda Science FoundationUNSPECIFIED
Canadian Institutes of Health Research (CIHR)324932
Columbia UniversityUNSPECIFIED
Pew Charitable Trust00031379
Issue or Number:6431
PubMed Central ID:PMC6708280
Record Number:CaltechAUTHORS:20190307-133956667
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190307-133956667
Official Citation:Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis. BY MARK S. LADINSKY, LEANDRO P. ARAUJO, XIAO ZHANG, JOHN VELTRI, MARTA GALAN-DIEZ, SALIMA SOUALHI, CAROLYN LEE, KOICHIRO IRIE, ELISHA Y. PINKER, SEIKO NARUSHIMA, SHEILA BANDYOPADHYAY, MANABU NAGAYAMA, WAEL ELHENAWY, BRIAN K. COOMBES, RONALDO P. FERRARIS, KENYA HONDA, ILIYAN D. ILIEV, NAN GAO, PAMELA J. BJORKMAN, IVAYLO I. IVANOV SCIENCE 08 MAR 2019; DOI: 10.1126/science.aat4042
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:93639
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:07 Mar 2019 23:01
Last Modified:06 Apr 2020 22:34

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