Loss of vascular endothelial notch signaling promotes spontaneous formation of tertiary lymphoid structures

Susanne Fleig, Tamar Kapanadze, Jeremiah Bernier-Latmani, Julia K. Lill, Tania Wyss, Jaba Gamrekelashvili, Dustin Kijas, Bin Liu, Anne M. Hüsing, Esther Bovay, Adan Chari Jirmo, Stephan Halle, Melanie Ricke-Hoch, Ralf H. Adams, Daniel R. Engel, Sibylle Vietinghoff, Reinhold Förster, Denise Hilfiker-Kleiner, Hermann Haller, Tatiana V. Petrova and Florian P. Limbourg ()
Additional contact information
Susanne Fleig: Hannover Medical School
Tamar Kapanadze: Hannover Medical School
Jeremiah Bernier-Latmani: Department of Oncology UNIL CHUV and Ludwig Institute for Cancer Research
Julia K. Lill: University Hospital Essen
Tania Wyss: Department of Oncology UNIL CHUV and Ludwig Institute for Cancer Research
Jaba Gamrekelashvili: Hannover Medical School
Dustin Kijas: Hannover Medical School
Bin Liu: Member of the German Center for Lung Research (DZL)
Anne M. Hüsing: Hannover Medical School
Esther Bovay: Max-Planck-Institute for Molecular Biomedicine
Adan Chari Jirmo: Member of the German Center for Lung Research (DZL)
Stephan Halle: Hannover Medical School
Melanie Ricke-Hoch: Hannover Medical School
Ralf H. Adams: Max-Planck-Institute for Molecular Biomedicine
Daniel R. Engel: University Hospital Essen
Sibylle Vietinghoff: Hannover Medical School
Reinhold Förster: Hannover Medical School
Denise Hilfiker-Kleiner: Hannover Medical School
Hermann Haller: Hannover Medical School
Tatiana V. Petrova: Department of Oncology UNIL CHUV and Ludwig Institute for Cancer Research
Florian P. Limbourg: Hannover Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Tertiary lymphoid structures (TLS) are lymph node-like immune cell clusters that emerge during chronic inflammation in non-lymphoid organs like the kidney, but their origin remains not well understood. Here we show, using conditional deletion strategies of the canonical Notch signaling mediator Rbpj, that loss of endothelial Notch signaling in adult mice induces the spontaneous formation of bona fide TLS in the kidney, liver and lung, based on molecular, cellular and structural criteria. These TLS form in a stereotypical manner around parenchymal arteries, while secondary lymphoid structures remained largely unchanged. This effect is mediated by endothelium of blood vessels, but not lymphatics, since a lymphatic endothelial-specific targeting strategy did not result in TLS formation, and involves loss of arterial specification and concomitant acquisition of a high endothelial cell phenotype, as shown by transcriptional analysis of kidney endothelial cells. This indicates a so far unrecognized role for vascular endothelial cells and Notch signaling in TLS initiation.

Date: 2022
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DOI: 10.1038/s41467-022-29701-x

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