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AG Immune Regulation

Group Leader: Dr. Carlos Plaza Sirvent

Our immune system is a master of balance—powerful enough to fight infections and cancer, yet precise enough to avoid attacking our own tissues. When this balance is lost, the consequences can be serious, leading to autoimmune diseases, chronic inflammation, or uncontrolled tumor growth.

At the Immune Regulation Research Group, we study one of the immune system’s most important “peacekeepers”: regulatory T cells (Tregs). These specialized cells act as brakes on the immune response, preventing excessive or misdirected attacks. Understanding how Tregs work—and how their activity is controlled—is key to developing new ways to treat a wide range of diseases.

Our research combines fundamental immunology with translational applications. We investigate the cell-signaling pathways that determine how Tregs survive, function, and adapt to different environments. A major focus is on cell death-related mechanisms—such as apoptosis, necroptosis, and autophagy—and how these processes shape immune regulation.

In recent years, we have expanded our work beyond the lab bench to address clinical challenges. We have studied immune responses to SARS-CoV-2 vaccination, collaborated with neurologists to explore autoimmune components of multiple sclerosis, and launched our own projects on neuromuscular diseases.

Our expertise in cell death and immune signaling has also led to exciting interdisciplinary collaborations, where we investigate immunogenic cell death triggered by metal complexes as potential cancer therapies.

By bridging basic science and clinical research, our goal is to uncover the molecular “switches” that control immune balance and to translate these discoveries into innovative treatments for cancer, autoimmune disorders, and infectious diseases.

Plaza-Sirvent C, Bessen C, Bronietzki AW, Klages K, Schuster M, Huehn J, Schmitz I. Loss of ATG5 impairs CD4+ T cell activation and promotes anti-tumor responses. Front Immunol. 2025 Sep 4;16:1284391. doi: 10.3389/fimmu.2025.1284391.

Papadopoulos Z, Antar Y, Dieter IS, Peeters F, Plaza-Sirvent C*, Karges J*. Gallium(III) Complex Induces Immunogenic Cell Death Hallmarks for Chemoimmunotherapy. J Med Chem. 2025;68(15):15980-15990. doi:10.1021/acs.jmedchem.5c00969

Plaza-Sirvent C, Sturm H, Nocke MK, Ghorbani F, Bessen C, Greweling-Pils MC, Floess S, Niemz J, Huysentruyt J, Tougaard P, Huehn J, Geffers R, Todt D, Vandenabeele P, Schmitz I. Ripk1 is critical for preserving effector regulatory T cells and the suppressive transcriptional program in regulatory T cells. Cell Death Differ. 2025 Jul 22. doi: 10.1038/s41418-025-01550-3. Online ahead of print.

Luu M, Krause FF, Monning H, Wempe A, Leister H, Mainieri L, Staudt S, Ziegler-Martin K, Mangold K, Kappelhoff N, Shaul YD, Göttig S, Plaza-Sirvent C, Schulte LN, Bekeredjian-Ding I, Schmitz I, Steinhoff U, Visekruna A. Dissecting the metabolic signaling pathways by which microbial molecules drive the differentiation of regulatory B cells. Mucosal Immunol. 2024 Sep 16:S1933-0219(24)00096-5. doi: 10.1016/j.mucimm.2024.09.003. Online ahead of print.

Bertazzon M, Hurtado-Pico A, Plaza-Sirvent C, Schuster M, Preußner M, Kuropka B, Liu F, Kirsten AZA, Schmitt XJ, König B, Álvaro-Benito M, Abualrous ET, Albert GI, Kliche S, Heyd F, Schmitz I, Freund C. The nuclear GYF protein CD2BP2/U5-52K is required for T cell homeostasis. Front Immunol. 2024 Sep 6;15:1415839. doi: 10.3389/fimmu.2024.1415839.

Simsek A, Bessen C, Meister TL, Urlaub D, Skaletz-Rorowski A, Brockmeyer NH, Overheu O, Reinacher-Schick A, Faissner S, Watzl C, Pfaender S, Schmitz I, Potthoff A, Plaza-Sirvent C. Humoral and cellular immune responses to repeated SARS-CoV-2 infection and vaccination in an individual living with HIV. J Eur Acad Dermatol Venereol. 2023 Mar 13. doi: 10.1111/jdv.19036.

Heinen N, Marheinecke CS, Bessen C, Blazquez-Navarro A, Roch T, Stervbo U, Anft M, Plaza-Sirvent C, Busse S, Klöhn M, Schrader J, Vidal Blanco E, Urlaub D, Watzl C, Hoffmann M, Pöhlmann S, Tenbusch M, Steinmann E, Todt D, Hagenbeck C, Zimmer G, Schmidt WE, Quast DR, Babel N, Schmitz I, Pfaender S. In-depth analysis of T cell immunity and antibody responses in heterologous prime-boost-boost vaccine regimens against SARS-CoV-2 and Omicron variant. Front Immunol. 2022 Dec 21;13:1062210. doi: 10.3389/fimmu.2022.1062210.

Bessen C, Plaza-Sirvent C, Simsek A, Bhat J, Marheinecke C, Urlaub D, Bonowitz P, Busse S, Schumann S, Blanco EV, Skaletz-Rorowski A, Brockmeyer NH, Overheu O, Reinacher-Schick A, Faissner S, Watzl C, Pfaender S, Potthoff A, Schmitz I. Impact of SARS-CoV-2 vaccination on systemic immune responses in people living with HIV. Front Immunol. 2022 Dec 2;13:1049070. doi: 10.3389/fimmu.2022.1049070.

Faissner S, Heitmann N, Rohling R, Ceylan U, Bongert M, Plaza-Sirvent C, Marheinecke C, Pedreiturria X, Ayzenberg I, Hellwig K, Schmitz I, Pfaender S, Gold R. Preserved T-cell response in anti-CD20-treated multiple sclerosis patients following SARS-CoV-2 vaccination. Ther Adv Neurol Disord. 2022 Dec 9;15:17562864221141505. doi: 10.1177/17562864221141505.

Faissner S, Heitmann N, Plaza-Sirvent C, Trendelenburg P, Ceylan U, Motte J, Bessen C, Urlaub D, Watzl C, Overheu O, Reinacher-Schick A, Hellwig K, Pfaender S, Schmitz I, Gold R. Immune response in ofatumumab treated multiple sclerosis patients after SARS-CoV-2 vaccination. Front Immunol. 2022 Aug 31;13:980526. doi: 10.3389/fimmu.2022.980526.

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.

Carriche GM, Almeida L, Stüve P, Velasquez L, Dhillon-LaBrooy A, Roy U, Lindenberg M, Stowig T, Plaza-Sirvent C, Schmitz I, Lochner M, Simon AK, Sparwasser T. Regulating T-cell differentiation through the polyamine spermidine. J Allergy Clin Immunol. 2021 Jan;147(1):335-348.e11. doi:10.1016/j.jaci.2020.04.037

Plaza-Sirvent C, Zhao B, Bronietzki AW, Pils MC, Tafrishi N, Schuster M, Strowig T, Schmitz I (2021) A Central Role for Atg5 in Microbiota-Dependent Foxp3+ RORγt+ Treg Cell Preservation to Maintain Intestinal Immune Homeostasis. Front Immunol. 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):2188.

Bank U, Deiser K, Plaza-Sirvent C, Osbelt L, Witte A, Knop L, Labrenz R, Jänsch R, Richter F, Biswas A, Zenclussen AC, Vivier E, Romagnani C, Kühl AA, Dunay IR, Strowig T, Schmitz I, Schüler T. c-FLIP is crucial for IL-7/IL-15-dependent NKp46+ ILC development and protection from intestinal inflammation in mice. Nat Commun. 2020 Feb 26;11(1):1056. 

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

Luebke T, Schwarz L, Beer YY, Schumann S, Misterek M, Sander FE, Plaza-Sirvent C, Schmitz I. c-FLIP and CD95 signaling are essential for survival of renal cell carcinoma. Cell Death Dis. 2019 May 16;10(6):384.

Chaudhry MZ, Kasmapour B, Plaza-Sirvent C, Bajagic M, Casalegno Garduño R, Borkner L, Lenac Roviš T, Scrima A, Jonjic S, Schmitz I, Cicin-Sain L. UL36 Rescues Apoptosis Inhibition and In vivo Replication of a Chimeric MCMV Lacking the M36 Gene. Front Cell Infect Microbiol. 2017 Jul 14;7:312.

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.

Plaza-Sirvent C, Schuster M, Neumann Y, Heise U, Pils MC, Schulze-Osthoff K, Schmitz I. c-FLIP Expression in Foxp3-Expressing Cells Is Essential for Survival of Regulatory T Cells and Prevention of Autoimmunity. Cell Rep. 2017 Jan 3;18(1):12-22.

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.

Ewald F, Annemann M, Pils MC, Plaza-Sirvent C, Neff F, Erck C, Reinhold D, Schmitz I. Constitutive expression of murine c-FLIPR causes autoimmunity in aged mice. Cell Death Dis. 2014 Apr 10;5(4):e1168.

Schuster M, Glauben R, Plaza-Sirvent C, Schreiber L, Annemann M, Floess S, Kühl AA, Clayton LK, Sparwasser T, Schulze-Osthoff K, Pfeffer K, Huehn J, Siegmund B, Schmitz I. IκB(NS) protein mediates regulatory T cell development via induction of the Foxp3 transcription factor. Immunity. 2012 Dec 14;37(6):998-1008.