Unsupervised High-Dimensional Analysis Aligns Dendritic Cells across Tissues and Species

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Summary

Dendritic cells (DCs) are professional antigen-presenting cells that hold great therapeutic potential. Multiple DC subsets have been described, and it remains challenging to align them across tissues and species to analyze their function in the absence of macrophage contamination. Here, we provide and validate a universal toolbox for the automated identification of DCs through unsupervised analysis of conventional flow cytometry and mass cytometry data obtained from multiple mouse, macaque, and human tissues. The use of a minimal set of lineage-imprinted markers was sufficient to subdivide DCs into conventional type 1 (cDC1s), conventional type 2 (cDC2s), and plasmacytoid DCs (pDCs) across tissues and species. This way, a large number of additional markers can still be used to further characterize the heterogeneity of DCs across tissues and during inflammation. This framework represents the way forward to a universal, high-throughput, and standardized analysis of DC populations from mutant mice and human patients.

Graphical Abstract

Highlights

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A conserved gating strategy aligns dendritic cells (DCs) in mouse and human tissues
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Unsupervised computational analysis of flow cytometry data outperforms manual analysis
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Mass cytometry reveals heterogeneity of DC subsets across mouse and human tissues
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DC activation upon inflammation tracked by automated analysis of mass cytometry

Abstract

Using unsupervised analysis of flow cytometry and mass cytometry data obtained from multiple mouse, macaque, and human tissues, Guilliams et al. provide a universal toolbox for the automated identification of dendritic cells. This framework represents the way forward to high-throughput and standardized analysis of dendritic cells from mutant mice and patients.

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Most cited references 32

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Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen.

Maud Plantinga, Martin Guilliams, Manon Vanheerswynghels … (2013)

Dendritic cells (DCs) are crucial for mounting allergic airway inflammation, but it is unclear which subset of DCs performs this task. By using CD64 and MAR-1 staining, we reliably separated CD11b(+) monocyte-derived DCs (moDCs) from conventional DCs (cDCs) and studied antigen uptake, migration, and presentation assays of lung and lymph node (LN) DCs in response to inhaled house dust mite (HDM). Mainly CD11b(+) cDCs but not CD103(+) cDCs induced T helper 2 (Th2) cell immunity in HDM-specific T cells in vitro and asthma in vivo. Studies in Flt3l(-/-) mice, lacking all cDCs, revealed that moDCs were also sufficient to induce Th2 cell-mediated immunity but only when high-dose HDM was given. The main function of moDCs was the production of proinflammatory chemokines and allergen presentation in the lung during challenge. Thus, we have identified migratory CD11b(+) cDCs as the principal subset inducing Th2 cell-mediated immunity in the LN, whereas moDCs orchestrate allergic inflammation in the lung. Copyright © 2013 Elsevier Inc. All rights reserved.

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Notch–RBP-J signaling controls the homeostasis of CD8− dendritic cells in the spleen

Michele Caton, Matthew R Smith-Raska, Boris Reizis (2007)

Signaling through Notch receptors and their transcriptional effector RBP-J is essential for lymphocyte development and function, whereas its role in other immune cell types is unclear. We tested the function of the canonical Notch–RBP-J pathway in dendritic cell (DC) development and maintenance in vivo. Genetic inactivation of RBP-J in the bone marrow did not preclude DC lineage commitment but caused the reduction of splenic DC fraction. The inactivation of RBP-J in DCs using a novel DC-specific deleter strain caused selective loss of the splenic CD8− DC subset and reduced the frequency of cytokine-secreting CD8− DCs after challenge with Toll-like receptor ligands. In contrast, other splenic DC subsets and DCs in the lymph nodes and tissues were unaffected. The RBP-J–deficient splenic CD8− DCs were depleted at the postprogenitor stage, exhibited increased apoptosis, and lost the expression of the Notch target gene Deltex1. In the spleen, CD8− DCs were found adjacent to cells expressing the Notch ligand Delta-like 1 in the marginal zone (MZ). Thus, canonical Notch–RBP-J signaling controls the maintenance of CD8− DCs in the splenic MZ, revealing an unexpected role of the Notch pathway in the innate immune system.

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The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8α+ dendritic cells

Karine Crozat, Rachel Guiton, Vanessa Suarez-Contreras … (2010)

Human BDCA3+ dendritic cells (DCs) were suggested to be homologous to mouse CD8α+ DCs. We demonstrate that human BDCA3+ DCs are more efficient than their BDCA1+ counterparts or plasmacytoid DCs (pDCs) in cross-presenting antigen and activating CD8+ T cells, which is similar to mouse CD8α+ DCs as compared with CD11b+ DCs or pDCs, although with more moderate differences between human DC subsets. Yet, no specific marker was known to be shared between homologous DC subsets across species. We found that XC chemokine receptor 1 (XCR1) is specifically expressed and active in mouse CD8α+, human BDCA3+, and sheep CD26+ DCs and is conserved across species. The mRNA encoding the XCR1 ligand chemokine (C motif) ligand 1 (XCL1) is selectively expressed in natural killer (NK) and CD8+ T lymphocytes at steady-state and is enhanced upon activation. Moreover, the Xcl1 mRNA is selectively expressed at high levels in central memory compared with naive CD8+ T lymphocytes. Finally, XCR1−/− mice have decreased early CD8+ T cell responses to Listeria monocytogenes infection, which is associated with higher bacterial loads early in infection. Therefore, XCR1 constitutes the first conserved specific marker for cell subsets homologous to mouse CD8α+ DCs in higher vertebrates and promotes their ability to activate early CD8+ T cell defenses against an intracellular pathogenic bacteria.

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Author and article information

Contributors

Martin Guilliams

Bart N. Lambrecht

Bernard Malissen

Florent Ginhoux

Journal

Journal ID (nlm-ta): Immunity

Journal ID (iso-abbrev): Immunity

Title: Immunity

Publisher: Cell Press

ISSN (Print): 1074-7613

ISSN (Electronic): 1097-4180

Publication date PMC-release: 20 September 2016

Publication date (Print): 20 September 2016

Volume: 45

Issue: 3

Pages: 669-684

Affiliations

[1 ]Unit of Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, Ghent 9052, Belgium

[2 ]Department of Biomedical Molecular Biology, Ghent University, Ghent 9000, Belgium

[3 ]Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, Inserm, CNRS, 13288 Marseille, France

[4 ]Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A ^∗STAR), 8A Biomedical Grove, IMMUNOS Building #3-4, BIOPOLIS, Singapore 138648, Singapore

[5 ]Program in Emerging Infectious Disease, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore

[6 ]Department of Information Technology, iMinds, Ghent University, Ghent 9000, Belgium

[7 ]Data Mining and Modeling for Biomedicine, VIB Inflammation Research Center, Ghent 9052, Belgium

[8 ]Department of Internal Medicine, Ghent University, Ghent 9000, Belgium

[9 ]Experimental Fetal Medicine Group, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore

[10 ]Department of Surgery, Yong Loo Lin School of Medicine, National University Singapore, Singapore 119077, Singapore

[11 ]Department of Pathology, National University of Singapore, Singapore 119077, Singapore

[12 ]K.G. Jebsen Centre for Influenza Vaccine Research, Oslo University Hospital, University of Oslo, 0027 Oslo, Norway

[13 ]Center for Immune Regulation, Institute of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, 0424 Oslo, Norway

[14 ]Department of Reproductive Medicine, Division of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, Singapore 229899, Singapore

[15 ]Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 119077, Singapore

[16 ]Centre d'Immunophénomique, Aix Marseille Université, Inserm, CNRS, 13288 Marseille, France

[17 ]Department of Pulmonary Medicine, Erasmus MC Rotterdam, Dr Molewaterplein 50, Rotterdam 3015 GE, The Netherlands

Author notes

[∗ ]Corresponding author martin.guilliams@ 123456irc.vib-ugent.be

[∗∗ ]Corresponding author bart.lambrecht@ 123456irc.vib-ugent.be

[∗∗∗ ]Corresponding author bernardm@ 123456ciml.univ-mrs.fr

[∗∗∗∗ ]Corresponding author florent_ginhoux@ 123456immunol.a-star.edu.sg

[18]

Co-first author

[19]

Lead Contact

Article

Publisher ID: S1074-7613(16)30339-9

DOI: 10.1016/j.immuni.2016.08.015

PMC ID: 5040826

PubMed ID: 27637149

SO-VID: 8614400d-161a-4ea9-a9d9-950989c0d571

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 20 January 2016

Date revision received : 2 June 2016

Date accepted : 7 July 2016

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Unsupervised High-Dimensional Analysis Aligns Dendritic Cells across Tissues and Species

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Gamma Delta T cells

Most cited references 32

Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen.

Notch–RBP-J signaling controls the homeostasis of CD8− dendritic cells in the spleen

The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8α+ dendritic cells

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Cited by 350

Most referenced authors 616