Intestinal fibroblastic reticular cell niches control innate lymphoid cell homeostasis and function

Hung-Wei Cheng, Urs Mörbe, Mechthild Lütge, Céline Engetschwiler, Lucas Onder, Mario Novkovic, Cristina Gil-Cruz, Christian Perez-Shibayama, Thomas Hehlgans, Elke Scandella and Burkhard Ludewig ()
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Hung-Wei Cheng: Kantonsspital St. Gallen
Urs Mörbe: Kantonsspital St. Gallen
Mechthild Lütge: Kantonsspital St. Gallen
Céline Engetschwiler: Kantonsspital St. Gallen
Lucas Onder: Kantonsspital St. Gallen
Mario Novkovic: Kantonsspital St. Gallen
Cristina Gil-Cruz: Kantonsspital St. Gallen
Christian Perez-Shibayama: Kantonsspital St. Gallen
Thomas Hehlgans: University of Regensburg
Elke Scandella: Kantonsspital St. Gallen
Burkhard Ludewig: Kantonsspital St. Gallen

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Innate lymphoid cells (ILCs) govern immune cell homeostasis in the intestine and protect the host against microbial pathogens. Various cell-intrinsic pathways have been identified that determine ILC development and differentiation. However, the cellular components that regulate ILC sustenance and function in the intestinal lamina propria are less known. Using single-cell transcriptomic analysis of lamina propria fibroblasts, we identify fibroblastic reticular cells (FRCs) that underpin cryptopatches (CPs) and isolated lymphoid follicles (ILFs). Genetic ablation of lymphotoxin-β receptor expression in Ccl19-expressing FRCs blocks the maturation of CPs into mature ILFs. Interactome analysis shows the major niche factors and processes underlying FRC-ILC crosstalk. In vivo validation confirms that a sustained lymphotoxin-driven feedforward loop of FRC activation including IL-7 generation is critical for the maintenance of functional ILC populations. In sum, our study indicates critical fibroblastic niches within the intestinal lamina propria that control ILC homeostasis and functionality and thereby secure protective gut immunity.

Date: 2022
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DOI: 10.1038/s41467-022-29734-2

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