Zhang, Lili: Dendritic Cell Type 2 Dictates Subtissular Localisation and Instructs Their Survival via the Thymic Stromal Lymphopoietin (TSLP) – TSLP Receptor (TSLPR) Axis. - Bonn, 2021. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-62931
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-62931,
author = {{Lili Zhang}},
title = {Dendritic Cell Type 2 Dictates Subtissular Localisation and Instructs Their Survival via the Thymic Stromal Lymphopoietin (TSLP) – TSLP Receptor (TSLPR) Axis},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2021,
month = jul,

note = {Introduction: G protein-coupled receptor 183 (GPR183) is a chemotactic receptor, highly expressed by immune cells. Upon activation by its ligand, 7a,25-dihydroxycholesterol (7a,25-OHC), GPR183 activates downstream signals inducing a wide range of functional responses, including inflammation, cell migration, and proliferation. Earlier work has shown that GPR183 is critical for the correct positioning of splenic dendritic cells (DCs) and the initiation of subsequent DC dependent adaptive immune responses. Whether GPR183 has a role in the localization and function of DCs in the murine lung has not been investigated.
Method: To understand its role in lung DC homeostasis and development we analyzed the abundance and phenotype of lung dendritic and stromal cell populations in WT and GPR183 KO animals using high dimensional flow cytometry alongside transcriptomic, functional and spatial analysis.
Results: We found that the absence of GPR183 resulted in a specific decrease of the resident pulmonary cDC2 population due to impaired in situ proliferation and increased apoptosis. In contrast, DC development was not affected by GPR183 ablation. Furthermore, analysis of the CH25H deficient mice revealed that CH25H dependent production of 7a,25-OHC is crucial for pulmonary cDC2 homeostasis. Adventitial fibroblasts are the major producer of 7a,25-OHC in the lung. Therefore we assessed the subtissular location of pulmonary cDC2 in the lung. This analysis revealed that cDC2 closely associate, in a GPR183 dependent manner, with adventitial fibroblasts. Next using single-cell transcriptomic data and cellular interaction modeling, we identified the thymic stromal lymphopoietin (TSLP) – TSLP receptor (TSLPR) axis as a possible candidate promoting cDC2 survival in a GPR183 dependent manner. Accordingly, DC-specific TSLPR KO mice had decreased pulmonary cDC2s numbers.
Conclusion: Collectively these findings demonstrate that GPR183 plays an intrinsic role in cDC2 maintenance and reveals GPR183 as a crucial regulator of peripheral organ resident DCs homeostasis and subtissular location. What is more, GPR183 – 7a,25-OHC acts as a guiding axis for pulmonary cDC2 localizing in their supporting subtissular niche where cDC2s have access to pro-survival factors such as TSLP – TSLPR instructed by fibroblasts.},

url = {https://hdl.handle.net/20.500.11811/9198}

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