Posttranslational modifications by ADAM10 shape myeloid antigen-presenting cell homeostasis in the splenic marginal zone

Proceedings of the National Academy of Sciences, vol. 118

Abstract

Significance Conventional dendritic cells (cDC) and macrophages display a high phenotypic and functional heterogeneity. ADAM10 regulates diverse cellular activities via so-called ectodomain shedding of cell-surface proteins. Here, we report that mice with a CD11c-specific deletion of ADAM10 exhibit defective cDC subset homeostasis in the splenic marginal zone (MZ). Specifically, ESAM hi cDC2A are replaced by a CX3CR1 + cDC2B population, and terminal differentiation of cDC1 is abrogated. Moreover, absent ADAM10 leads to the selective expansion of marginal metallophilic macrophages. Thus, ADAM10 represents an essential molecular switch on splenic antigen-presenting cells, shaping the anatomical niche of the MZ. Thereby, ADAM10-mediated posttranslational processes constitute a pathway beyond the usual and well-characterized transcriptional decisions governing tissue-specific cDC and macrophage subset commitment and homeostasis.

Authors 12

1. Nathalie Diener

   Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Institute for Molecular Medicine, Paul Klein Center for Immune Intervention, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;

2. Jean−Fred Fontaine

   Johannes Gutenberg University Mainz

   Affiliation as printed

   iOME Computational Biology and Data Mining, Johannes Gutenberg-University, 55128 Mainz, Germany;

3. Matthias Klein

   Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Institute for Immunology, Paul Klein Center for Immune Intervention, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;

   Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;

4. Thomas Hieronymus Aachen Department of Cell Biology Institute for Biomedical Engineering

   RWTH Aachen University

   Affiliation as printed

   Department of Cell Biology, Institute for Biomedical Engineering, Rheinisch-Westfälische Technische Hochschule Aachen, University Medical Center, 52074 Aachen, Germany;

5. Florian Wanke

   Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Institute for Molecular Medicine, Paul Klein Center for Immune Intervention, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;

6. Florian C. Kurschus

   Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Institute for Molecular Medicine, Paul Klein Center for Immune Intervention, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;

7. Andreas Ludwig Aachen Institute of Pharmacology and Toxicology

   RWTH Aachen University

   Affiliation as printed

   Institute of Pharmacology and Toxicology, Rheinisch-Westfälische Technische Hochschule Aachen, University Medical Center, 52074 Aachen, Germany;

8. Carl F. Ware

   Sanford Burnham Prebys Medical Discovery Institute

   Affiliation as printed

   Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037;

9. Paul Säftig

   Christian-Albrechts-Universität zu Kiel

   Affiliation as printed

   Institute of Biochemistry, Christian-Albrechts-University Kiel, 24098 Kiel, Germany

10. Tobias Bopp

    Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

    Affiliation as printed

    Institute for Immunology, Paul Klein Center for Immune Intervention, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;

    Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;

11. Björn E. Clausen corresponding

    Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

    Affiliation as printed

    Institute for Molecular Medicine, Paul Klein Center for Immune Intervention, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;

    Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;

12. Ronald A. Backer corresponding

    Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

    Affiliation as printed

    Institute for Molecular Medicine, Paul Klein Center for Immune Intervention, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;

    Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany;