Posttranslational modifications by ADAM10 shape myeloid antigen-presenting cell homeostasis in the splenic marginal zone
Nathalie Diener, Jean−Fred Fontaine, Matthias Klein, Thomas Hieronymus, Florian Wanke, Florian C. Kurschus, Andreas Ludwig, Carl F. Ware, Paul Säftig, Tobias Bopp, Björn E. Clausen, Ronald A. Backer
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.