AG Transcription and Immune- cell differentiation

Group Leader: Prof. Dr. Ingo Schmitz

The pro-inflammatory transcription factor NF-kB plays a pivotal role in the activation of immune cells. Its activity is e.g. inhibited by glucocorticoids and cortisol derivatives are the most widely used immunosuppressive drugs. NF-kB is not only important for inflammatory processes, but also during development of immune cells and in the regulation of life and death. Thus, general inhibition of NF-kB is usually toxic to cells and a more precise inhibition is required. Here, atypical inhibitors of NF-kB (IkB) proteins might prove to be interesting targets. We investigate the role of atypical IkB proteins and NF-kB in the development and function of immune cells. To this end, we have established several mouse models (transgenic, knockout, Cre/lox system). Moreover, we apply multicolor flow cytometry using a high-end FACS analyzer. At the molecular level, we analyze target genes of atypical IkB proteins and employ RNA-seq and chromatin immunoprecipitation. Bioinformatics is utilized to analyze the data.

Köhler A, Geiselhöringer AL, Kolland D, Kreft L, Wichmann N, Hils M, Pasztoi M, Zurkowski E, Vogt J, Kübelbeck T, Biedermann T, Schmitz I, Hansen W, Kramer D, Gaida MM, Schmidt-Weber CB, Hoevelmeyer N, Ohnmacht C. The atypical IκB family member Bcl3 determines differentiation and fate of intestinal RORγt+ regulatory T-cell subsets. Mucosal Immunol. 2024 Apr 23:S1933-0219(24)00039-4. doi: 10.1016/j.mucimm.2024.04.002

Schmidt H, Raj T, O'Neill TJ, Muschaweckh A, Giesert F, Negraschus A, Hoefig KP, Behrens G, Esser L, Baumann C, Feederle R, Plaza-Sirvent C, Geerlof A, Gewies A, Isay SE, Ruland J, Schmitz I, Wurst W, Korn T, Krappmann D, Heissmeyer V. Unrestrained cleavage of Roquin-1 by MALT1 induces spontaneous T cell activation and the development of autoimmunity. Proc Natl Acad Sci U S A. 2023 Nov 28;120(48):e2309205120. doi: 10.1073/pnas.2309205120.

Frentzel S, Jeron A, Pausder A, Kershaw O, Volckmar J, Schmitz I, Bruder D. IκBNS-deficiency protects mice from fatal Listeria monocytogenes infection by blunting pro-inflammatory signature in Ly6Chigh monocytes and preventing exaggerated innate immune responses. Front Immunol. 2022 Dec 22;13:1028789. doi: 10.3389/fimmu.2022.1028789.

Dwyer JR, Racine JJ, Chapman HD, Quinlan A, Presa M, Stafford GA, Schmitz I, Serreze DV. 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. J Immunol. 2022 Jul 15;209(2):227-237. doi: 10.4049/jimmunol.2100558.

Kästle M, Merten C, Hartig R, Plaza-Sirvent C, Schmitz I, Bommhardt U, Schraven B, Simeoni L. Y192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-γ1 and Thymic Selection. Int J Mol Sci. 2022 Jun 30;23(13):7271. doi: 10.3390/ijms23137271.

Schmitz I. Gadd45 Proteins in Immunity 2.0. Adv Exp Med Biol. 2022, May 04, 1360:69-86. doi: 10.1007/978-3-030-94804-7_5.

Plaza-Sirvent C, Zhao B, Bronietzki AW, Pils MC, Tafrishi N, Schuster M, Strowig T, Schmitz I. A Central Role for Atg5 in Microbiota-Dependent Foxp3+ RORγt+ Treg Cell Preservation to Maintain Intestinal Immune Homeostasis. Front Immunol. 2021 12:705436. doi: 10.3389/fimmu.2021.705436

Shah A, Plaza-Sirvent C, Weinert S, Buchbinder JH, Lavrik IN, Mertens PR, Schmitz I*, Lindquist JA*. YB-1 Mediates TNF-Induced Pro-Survival Signaling by Regulating NF-κB Activation. Cancers (Basel). 2020 Aug 5;12(8):E2188.

* equal contribution

Luu M, Romero R, Bazant J, Abass E, Hartmann S, Leister H, Fischer F, Mahdavi R, Plaza-Sirvent C, Schmitz I, Steinhoff U, Visekruna A. The NF-κB transcription factor c-Rel controls host defense against Citrobacter rodentium. Eur J Immunol.  2020 Feb;50(2):292-294.

Schuster M, Plaza-Sirvent C, Visekruna A, Huehn J, Schmitz I. Generation of Foxp3(+)CD25(-) Regulatory T-Cell Precursors Requires c-Rel and IκB(NS). Front Immunol. 2019 Jul 10;10:1583.

Frentzel S, Katsoulis-Dimitriou K, Jeron A, Schmitz I*, Bruder D*. Essential role of IκB(NS) for in vivo CD4(+) T-cell activation, proliferation, and Th1-cell differentiation during Listeria monocytogenes infection in mice. Eur J Immunol. 2019 Sep;49(9):1391-1398.

* = both authors contributed equally to this work

Presa M, Racine JJ, Dwyer JR, Lamont DJ, Ratiu JJ, Sarsani VK, Chen YG, Geurts A, Schmitz I, Stearns T, Allocco J, Chapman HD, Serreze DV. A Hypermorphic Nfkbid Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8(+) T Cells in NOD Mice. J Immunol. 2018 Oct 1;201(7):1907-1917.

Schuster M, Plaza-Sirvent C, Matthies AM, Heise U, Jeron A, Bruder D, Visekruna A, Huehn J, Schmitz I. c-REL and IκBNS govern common and independent steps of regulatory T-cell development from novel CD122-expressing pre-precursors. J Immunol. 2017 Aug 1;199(3):920-930.

Annemann M, Plaza-Sirvent C, Schuster M, Katsoulis-Dimitriou K, Kliche S, Schraven B, Schmitz I. Atypical IκB proteins in immune cell differentiation and function. Immunol Lett. 2016 Mar;171:26-35.

Annemann M, Wang Z, Plaza-Sirvent C, Glauben R, Schuster M, Ewald Sander F, Mamareli P, Kühl AA, Siegmund B, Lochner M, Schmitz I. IκBNS Regulates Murine Th17 Differentiation during Gut Inflammation and Infection. J Immunol. 2015 Mar 15;194(6):2888-98.

Jeltsch KM, Hu D, Brenner S, Zöller J, Heinz GA, Nagel D, Vogel KU, Rehage N, Warth SC, Edelmann SL, Martin N, Lohs C, Maciej L, Stehklein JE, Geerlof A, Jäck HM, Kremmer E, Weber A, Anders HJ, Schmitz I, Schmidt-Supprian M, Fu M, Holtmann H, Krappmann D, Ruland J, Kallies A, Heikenwalder M, Heissmeyer V. The paracaspase Malt1 cleaves roquin and regnase-1 to release cooperatively repressed mRNAs that promote TH17 differentiation. Nat Immunol. 2014 Nov;15(11):1079-89.

Schreiber L, Pietzsch B, Floess S, Jänsch L, Schmitz I, Huehn J. The Treg-specific demethylated region stabilizes Foxp3 expression independently of NF-κB signaling. PLoS One. 2014 Feb 5;9(2):e88318

Schuster M, Annemann M, Plaza-Sirvent C, Schmitz I. Atypical IκB proteins – nuclear modulators of NFκB signaling. Cell Commun Signal. 2013 Apr 11;11(1):23.

Hildebrandt D, Alexander E, Hörber S, Lehle SPD, Obermayer K, Münck NA, Rothfuss O, Frick JS, Schmitz I, Roth J, Ehrchen JM, Essmann F, Schulze-Osthoff K. Inhibitor of NFκB (IkBζ) is a transcriptional key regulator of monocyte chemoattractant protein-1 (MCP-1/CCL2). J Immunol. 2013 190:4812-4820.

Schuster M, Glauben R, Plaza-Sirvent C, Schreiber L, Annemann M, Floess S, Kühl AA, Clayton LK, Sparwasser T, Schulze-Osthoff K, Hühn J, Siegmund B, Pfeffer K, Schmitz I. IkBNS Protein Mediates Regulatory T Cell Development via Induction of the Foxp3 Transcription Factor. Immunity 2012 Dec 14;37(6):998-1008.