Single-Cell Survey of Human Lymphatics Unveils Marked Endothelial Cell Heterogeneity and Mechanisms of Homing for Neutrophils

Akira Takeda; Maija Hollmén; Denis Dermadi; Junliang Pan; Kevin Francis Brulois; Riina Kaukonen; Tapio Lönnberg; Pia Boström; Ilkka Koskivuo; Heikki Irjala; Masayuki Miyasaka; Marko Salmi; Eugene C Butcher; Sirpa Jalkanen

doi:10.1016/j.immuni.2019.06.027

Single-Cell Survey of Human Lymphatics Unveils Marked Endothelial Cell Heterogeneity and Mechanisms of Homing for Neutrophils

Immunity. 2019 Sep 17;51(3):561-572.e5. doi: 10.1016/j.immuni.2019.06.027. Epub 2019 Aug 8.

Authors

Affiliations

¹ MediCity Research Laboratory and Institute of Biomedicine, University of Turku, Turku, Finland.
² Laboratory of Immunology and Vascular Biology, Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA.
³ Laboratory of Immunology and Vascular Biology, Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA; Veterans Affairs Palo Alto Health Care System and The Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
⁴ Turku Centre for Biotechnology, University of Turku, Turku, Finland.
⁵ Department of Pathology, Turku University Hospital, Turku, Finland.
⁶ Department of Plastic and General Surgery, Turku University Hospital, Turku, Finland.
⁷ Department of Otorhinolaryngology, Turku University Hospital and University of Turku, Finland.
⁸ MediCity Research Laboratory and Institute of Biomedicine, University of Turku, Turku, Finland; Interdisciplinary Program for Biomedical Sciences, Institute for Academic Initiatives, Osaka University, Suita, Japan.
⁹ MediCity Research Laboratory and Institute of Biomedicine, University of Turku, Turku, Finland. Electronic address: sirjal@utu.fi.

PMID: 31402260
DOI: 10.1016/j.immuni.2019.06.027

Abstract

Lymphatic vessels form a critical component in the regulation of human health and disease. While their functional significance is increasingly being recognized, the comprehensive heterogeneity of lymphatics remains uncharacterized. Here, we report the profiling of 33,000 lymphatic endothelial cells (LECs) in human lymph nodes (LNs) by single-cell RNA sequencing. Unbiased clustering revealed six major types of human LECs. LECs lining the subcapsular sinus (SCS) of LNs abundantly expressed neutrophil chemoattractants, whereas LECs lining the medullary sinus (MS) expressed a C-type lectin CD209. Binding of a carbohydrate Lewis X (CD15) to CD209 mediated neutrophil binding to the MS. The neutrophil-selective homing by MS LECs may retain neutrophils in the LN medulla and allow lymph-borne pathogens to clear, preventing their spread through LNs in humans. Our study provides a comprehensive characterization of LEC heterogeneity and unveils a previously undefined role for medullary LECs in human immunity.

Keywords: cell adhesion; heterogeneity; human immunity; leukocyte trafficking; lymph nodes; lymphatic endothelial cells; lymphatic vessels; lymphatics; neutrophils; single-cell RNA-seq.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Adhesion Molecules / immunology
Cells, Cultured
Endothelial Cells / immunology*
Humans
Lectins, C-Type / immunology
Lewis X Antigen / immunology
Lymph Nodes / immunology
Lymphatic Vessels / immunology
Mice, Inbred C57BL
Neutrophils / immunology*
Receptors, Cell Surface / immunology
Surveys and Questionnaires

Substances

Cell Adhesion Molecules
DC-specific ICAM-3 grabbing nonintegrin
Lectins, C-Type
Lewis X Antigen
Receptors, Cell Surface

Grants and funding

U54 CA209971/CA/NCI NIH HHS/United States