title: Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy.
abstract: Dendritic cells are targeted by regulatory T (T reg) cells, in a manner that operates as an indirect mode of T cell suppression. In this study, using a combination of single-cell force spectroscopy and structured illumination microscopy, we analyze individual T reg cell-DC interaction events and show that T reg cells exhibit strong intrinsic adhesiveness to DCs. This increased DC adhesion reduces the ability of contacted DCs to engage other antigen-specific cells. We show that this unusually strong LFA-1-dependent adhesiveness of T reg cells is caused in part by their low calpain activities, which normally release integrin-cytoskeleton linkage, and thereby reduce adhesion. Super resolution imaging reveals that such T reg cell adhesion causes sequestration of Fascin-1, an actin-bundling protein essential for immunological synapse formation, and skews Fascin-1-dependent actin polarization in DCs toward the T reg cell adhesion zone. Although it is reversible upon T reg cell disengagement, this sequestration of essential cytoskeletal components causes a lethargic state of DCs, leading to reduced T cell priming. Our results reveal a dynamic cytoskeletal component underlying T reg cell-mediated DC suppression in a contact-dependent manner.
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 10084, China.|Institute for Immunology, School of Medicine, Tsinghua University, Beijing 10084, China.
authors.forename: Jiahuan
authors.identifier: 0000-0002-3492-9032
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, T2N 1N4 Alberta, Canada.
authors.forename: Anutosh
authors.identifier: 0000-0002-7228-7827
authors.initials: A
authors.lastname: Ganguly
authors.affiliation: Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, T2N 1N4 Alberta, Canada.
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Mucsi
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 10084, China.|Institute for Immunology, School of Medicine, Tsinghua University, Beijing 10084, China.
authors.forename: Junchen
authors.initials: J
authors.lastname: Meng
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 10084, China.|Institute for Immunology, School of Medicine, Tsinghua University, Beijing 10084, China.
authors.forename: Jiacong
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, T2N 1N4 Alberta, Canada.
authors.forename: Pascal
authors.identifier: 0000-0002-2210-5220
authors.initials: P
authors.lastname: Detampel
authors.affiliation: Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, T2N 1N4 Alberta, Canada.
authors.forename: Fay
authors.identifier: 0000-0002-8515-1814
authors.initials: F
authors.lastname: Munro
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 10084, China.|Institute for Immunology, School of Medicine, Tsinghua University, Beijing 10084, China.
authors.forename: Zongde
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 10084, China.|Institute for Immunology, School of Medicine, Tsinghua University, Beijing 10084, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, T2N 1N4 Alberta, Canada.
authors.forename: Aswin
authors.initials: A
authors.lastname: Hari
authors.affiliation: Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, T2N 1N4 Alberta, Canada.
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Stenner
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 10084, China.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Snyder Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 10084, China.|Institute for Immunology, School of Medicine, Tsinghua University, Beijing 10084, China.
authors.forename: Tie
authors.initials: T
authors.lastname: Xia
authors.affiliation: Department of Cell Biology and, Cumming School of Medicine, University of Calgary, Calgary, T2N 1N4 Alberta, Canada.|Department of Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 1N4, Canada.|Snyder Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Amrein
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 10084, China.|Institute for Immunology, School of Medicine, Tsinghua University, Beijing 10084, China.
authors.forename: Hai
authors.identifier: 0000-0001-5475-3989
authors.initials: H
authors.lastname: Qi
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 10084, China yanshi@biomed.tsinghua.edu.cn.|Institute for Immunology, School of Medicine, Tsinghua University, Beijing 10084, China.|Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, T2N 1N4 Alberta, Canada.|Snyder Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Yan
authors.identifier: 0000-0002-6715-7681
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002450:Cell Communication; D016764:Cell Polarity; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology*; D003713:Dendritic Cells / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000502:physiology; D018035:Receptors, Odorant / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000502:physiology*
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D008840:Microfilament Proteins; D018035:Receptors, Odorant; C544141:Olfr73 protein, mouse