Dominant immune tolerance in the intestinal tract imposed by RelB-dependent migratory dendritic cells regulates protective type 2 immunity

Anna-Lena Geiselhöringer, Daphne Kolland, Arisha Johanna Patt, Linda Hammann, Amelie Köhler, Luisa Kreft, Nina Wichmann, Miriam Hils, Christiane Ruedl, Marc Riemann, Tilo Biedermann, David Anz, Andreas Diefenbach, David Voehringer, Carsten B. Schmidt-Weber, Tobias Straub, Maria Pasztoi and Caspar Ohnmacht ()
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Anna-Lena Geiselhöringer: Technical University and Helmholtz Center Munich
Daphne Kolland: Technical University and Helmholtz Center Munich
Arisha Johanna Patt: Technical University and Helmholtz Center Munich
Linda Hammann: LMU
Amelie Köhler: Technical University and Helmholtz Center Munich
Luisa Kreft: Technical University and Helmholtz Center Munich
Nina Wichmann: Technical University and Helmholtz Center Munich
Miriam Hils: Technical University of Munich
Christiane Ruedl: Nanyang Technological University Singapore
Marc Riemann: Fritz Lipmann Institute
Tilo Biedermann: Technical University of Munich
David Anz: LMU
Andreas Diefenbach: Charité-Universitätsmedizin Berlin
David Voehringer: University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg (FAU)
Carsten B. Schmidt-Weber: Technical University and Helmholtz Center Munich
Tobias Straub: Ludwig-Maximilians-University
Maria Pasztoi: Technical University and Helmholtz Center Munich
Caspar Ohnmacht: Technical University and Helmholtz Center Munich

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3+ regulatory T cells (Treg cells). Here, we show that in the lamina propria of the small intestine, the alternative NF-κB family member RelB is necessary for the differentiation of cryptopatch and isolated lymphoid follicle-associated DCs (CIA-DCs). Moreover, single-cell RNA sequencing reveals a RelB-dependent signature in migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction including elevated expression and release of the chemokine CCL22 from RelB-deficient conventional DCs (cDCs). In line with the key role of CCL22 to facilitate DC-Treg cell interaction, RelB-deficient DCs have a selective advantage to interact with Treg cells in an antigen-specific manner. In addition, DC-specific RelB knockout animals show increased total Foxp3+ Treg cell numbers irrespective of inflammatory status. Consequently, DC-specific RelB knockout animals fail to mount protective Th2-dominated immune responses in the intestine after infection with Heligmosomoides polygyrus bakeri. Thus, RelB expression in cDCs acts as a rheostat to establish a tolerogenic set point that is maintained even during strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis.

Date: 2024
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DOI: 10.1038/s41467-024-53112-9

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