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Köhler, A. ; Geiselhöringer, A.-L. ; Kolland, D. ; Kreft, L. ; Wichmann, N. ; Hils, M.* ; Szente-Pasztoi, M. ; Zurkowski, E.* ; Vogt, J.* ; Kübelbeck, T.* ; Biedermann, T.* ; Schmitz, I.* ; Hansen, W.* ; Kramer, D.* ; Gaida, M.M.* ; Schmidt-Weber, C.B. ; Hoevelmeyer, N.* ; Ohnmacht, C.

The atypical IκB family member Bcl3 determines differentiation and fate of intestinal RORγt+ regulatory T cell subsets.

Mucosal Immunol. 17, 673-691 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Peripherally induced regulatory T cells (pTregs) expressing the retinoic acid receptor-related orphan-receptor gamma t (RORγt) are indispensable for intestinal immune homeostasis. NF-κB family members regulate the differentiation of thymic Tregs and promote their survival in the periphery. However, the Treg-intrinsic molecular mechanisms controling the size of the pTregs in the intestine and associated lymphoid organs remain unclear. Here, we provide direct evidence that Bcl3 limits the development of pTregs in a T cell-intrinsic manner. Moreover, the absence of Bcl3 allowed for the formation of an unusual intestinal Treg population co-expressing the transcription factors Helios and RORγt. The expanded RORγt+ Treg populations in the absence of Bcl3 displayed an activated phenotype and secreted high levels of the anti-inflammatory cytokines IL-10 and TGFβ. They were fully capable of suppressing effector T cells in a transfer colitis model despite an intrinsic bias to trans-differentiate toward Th17-like cells. Finally, we provide a Bcl3-dependent gene signature in pTregs including altered responsiveness to the cytokines IL-2, IL-6, and TNFα. Our results demonstrate that Bcl3 acts as a molecular switch to limit the expansion of different intestinal Treg subsets and may thus serve as a novel therapeutic target for inflammatory bowel disease by restoring intestinal immune tolerance.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Bcl3 ; Foxp3 ; Intestinal Tolerance ; Nf- κb ; Ror Gamma T ; Inflammatory Bowel Disease ; Regulatory T Cells; Proprotein Convertase Furin; Tolerance; Oncoprotein; Plasticity; Immunity; Receptor; Therapy; Lineage; Binding; Stat3
ISSN (print) / ISBN 1933-0219
e-ISSN 1933-0219
Journal Mucosal Immunology
Quellenangaben Volume: 17, Issue: 4, Pages: 673-691 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place UNITED STATES
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute for Allergy Research (IAF)
Grants German Research Foundation
European Research Council (ERC)