The role of c-Rel and IkappaBNS in T-cell activation and the differentiation of follicular T cells
Final Report Abstract
Our previous work demonstrated the role of IκBNS, an atypical inhibitor of NF-κB, in T cell proliferation and the differentiation of distinct CD4+ T helper (Th) cell subsets, including Th1, Th17, and regulatory T cells (Tregs). Th1 and Th17 cells require strong T cell receptor (TCR) signaling for their differentiation. Of note, IκBNS is strongly induced upon TCR activation. Follicular helper T cells (Tfh) represent a specialized subset of Th cells that play a crucial role in the humoral immune response by supporting B cell proliferation and differentiation into antibody-producing cells within germinal centers (GC). Tfh cell differentiation is driven by constitutively TCR signaling, both during their development and functional activity. The differentiation process occurs in a stepwise manner: first, through antigen presentation, leading to the generation of precursor Tfh cells (pre-Tfh), and later through interaction with cognate B cells, allowing full maturation into GC Tfh cells. Within the germinal center, GC Tfh cells promote B cell proliferation and antibody affinity maturation via receptor-ligand interactions, such as TCR-MHC II, ICOS-ICOSL, and CD40L-CD40 signaling, as well as through cytokine production and signaling, such as IL-21. Given the constant TCR stimulation required for Tfh differentiation and function, we hypothesized that IκBNS would be highly induced in Tfh cells and play a critical role in their development and function. As outlined in our DFG proposal, we aimed to investigate the role of IκBNS in Tfh differentiation across different organs, such as the spleen and Peyer’s patches.
Publications
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IκBNS-deficiency protects mice from fatal Listeria monocytogenes infection by blunting pro-inflammatory signature in Ly6Chigh monocytes and preventing exaggerated innate immune responses. Frontiers in Immunology, 13.
Frentzel, Sarah; Jeron, Andreas; Pausder, Alexander; Kershaw, Olivia; Volckmar, Julia; Schmitz, Ingo & Bruder, Dunja
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Nfkbid Overexpression in Nonobese Diabetic Mice Elicits Complete Type 1 Diabetes Resistance in Part Associated with Enhanced Thymic Deletion of Pathogenic CD8 T Cells and Increased Numbers and Activity of Regulatory T Cells. The Journal of Immunology, 209(2), 227-237.
Dwyer, Jennifer R.; Racine, Jeremy J.; Chapman, Harold D.; Quinlan, Anna; Presa, Maximiliano; Stafford, Grace A.; Schmitz, Ingo & Serreze, David V.
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Y192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-γ1 and Thymic Selection. International Journal of Molecular Sciences, 23(13), 7271.
Kästle, Matthias; Merten, Camilla; Hartig, Roland; Plaza-Sirvent, Carlos; Schmitz, Ingo; Bommhardt, Ursula; Schraven, Burkhart & Simeoni, Luca
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Unrestrained cleavage of Roquin-1 by MALT1 induces spontaneous T cell activation and the development of autoimmunity. Proceedings of the National Academy of Sciences, 120(48).
Schmidt, Henrik; Raj, Timsse; O.'Neill, Thomas J.; Muschaweckh, Andreas; Giesert, Florian; Negraschus, Arlinda; Hoefig, Kai P.; Behrens, Gesine; Esser, Lena; Baumann, Christina; Feederle, Regina; Plaza-Sirvent, Carlos; Geerlof, Arie; Gewies, Andreas; Isay, Sophie E.; Ruland, Jürgen; Schmitz, Ingo; Wurst, Wolfgang; Korn, Thomas ... & Heissmeyer, Vigo
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A special RELationship between sugar and tumor-infiltrating regulatory T cells. Cellular & Molecular Immunology, 22(3), 330-332.
Schmitz, Ingo
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The atypical IκB family member Bcl3 determines differentiation and fate of intestinal RORγt+ regulatory T-cell subsets. Mucosal Immunology, 17(4), 673-691.
Köhler, Amelie; Geiselhöringer, Anna-Lena; Kolland, Daphne; Kreft, Luisa; Wichmann, Nina; Hils, Miriam; Pasztoi, Maria; Zurkowski, Elena; Vogt, Johannes; Kübelbeck, Tanja; Biedermann, Tilo; Schmitz, Ingo; Hansen, Wiebke; Kramer, Daniela; Gaida, Matthias M.; Schmidt-Weber, Carsten B.; Hoevelmeyer, Nadine & Ohnmacht, Caspar
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Dissecting the metabolic signaling pathways by which microbial molecules drive the differentiation of regulatory B cells. Mucosal Immunology, 18(1), 66-75.
Luu, Maik; Krause, Felix F.; Monning, Heide; Wempe, Anne; Leister, Hanna; Mainieri, Lisa; Staudt, Sarah; Ziegler-Martin, Kai; Mangold, Kira; Kappelhoff, Nora; Shaul, Yoav D.; Göttig, Stephan; Plaza-Sirvent, Carlos; Schulte, Leon N.; Bekeredjian-Ding, Isabelle; Schmitz, Ingo; Steinhoff, Ulrich & Visekruna, Alexander
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The cell death regulator c-FLIPR impairs Natural Killer cell responses during Influenza A virus infection. Springer Science and Business Media LLC.
Carmo-Fernandes, André; Tafrishi, Neda; Katsoulis-Dimitriou, Konstantinos; Greweling-Pils, Marina C.; Bruder, Dunja; Plaza-Sirvent, Carlos & Schmitz, Ingo
