Nobel Prize in Immunology: How This Pioneering Work Shapes Our Research
10/16/2025Treg discovery revolutionized immunology. Our teams study their metabolism and function.
The discovery of regulatory T cells (Tregs) marks a true milestone in immunology. It has fundamentally changed our understanding of how the body protects and regulates itself. The Max Planck Research Group for Systems Immunology and the Institute of Systems Immunology at the University of Würzburg are investigating how cellular metabolism controls Treg function, what role tissue-resident Tregs play in different organs, and how intestinal Tregs regulate immune balance and inflammation.
Shimon Sakaguchi and the Discovery of Regulatory T Cells
As early as the 1970s, so-called suppressor cells were the focus of intensive research. However, for a long time, the field saw little progress. Many experiments led to inconclusive results, and the topic lost prestige. It was not until the mid-1990s that Shimon Sakaguchi brought new momentum to the research and revived interest in the area of immunoregulation. His first key paper appeared in The Journal of Immunology - not one of the high-impact journals - but its content was groundbreaking: Sakaguchi was the first to convincingly show that a small subset of CD4⁺ T cells exerts an immunosuppressive effect.
Equally significant was the work of Mary Brunkow and Fred Ramsdell, who identified the defective gene in the so-called Scurfy mice. Sequencing such a large genetic locus was an enormous technical challenge at the time. The gene they identified, Foxp3, was previously unknown – and turned out to be essential for the development and regulatory function of this special class of T cells. Brunkow and Ramsdell also discovered that the X-linked autoimmune disease IPEX is caused by mutations in this same gene.
Two years later, Sakaguchi succeeded in connecting these discoveries with his own observations. He was able to show that the Foxp3 gene controls the development of the very cells he had identified back in 1995. Thus, the work of Sakaguchi (at the cellular level) and Brunkow/Ramsdell (at the genetic level) complemented each other perfectly and led to a completely new understanding of how the immune system functions and regulates itself.
As is often the case in science, our current understanding of Tregs is not solely the result of these three pioneers - although their contributions were crucial. Once Sakaguchi’s discoveries had firmly established that Tregs truly exist and can be clearly identified by the transcription factor Foxp3, an entire generation of immunologists dedicated themselves to studying these cells. In addition to the Nobel laureates, numerous researchers, including Alexander Rudensky, Jeff Bluestone, Ethan Shevach, and many others, have made major contributions to the field. Together, they helped establish one of the most exciting areas of modern immunology and fundamentally expanded our understanding of the immune system.
Tregs: Metabolism and Immune Regulation
Tregs differ from other T cells not only in their roles within the immune system but also in their distinct metabolic profiles. In recent years, it has become evident that this metabolic program is crucial for both Treg development and the effectiveness of their regulatory functions. Tregs are involved in nearly all inflammatory processes. Moreover, they play an important role in maintaining tissue homeostasis, in tumor formation, and in other “tolerant” situations, such as during pregnancy or organ transplantation.
The research group led by Martin Vaeth at the Max Planck Research Group investigates how Tregs are regulated at the molecular and metabolic levels, and their adaptations to different tissue environments. The group aims to determine whether these adaptations can be purposefully manipulated - for example, to treat autoimmune diseases or cancer.
“When I started in science, the first genetic models and tools for studying Tregs were just being developed - some of which my lab still uses today. In that sense, I’m personally delighted about this Nobel Prize, since these cells have shaped my scientific career and remain fascinating,” says the researcher.
The Importance of Foxp3 in Tregs
The discovery that Foxp3 is an essential and specific transcription factor of Tregs represents a breakthrough for our research. This knowledge is of central importance, as it enables both the identification of Tregs and their targeted genetic manipulation and depletion.
“Despite this important finding, the precise mechanisms by which Tregs function are still not fully understood. Numerous mechanisms have been proposed to explain their immunosuppressive activity, but there is still no clear consensus on how Tregs actually suppress different immune responses,” explains Wolfgang Kastenmüller, head of the Max Planck Research Group.
To address these open questions, his group employs various Foxp3-based animal models. These include fluorescent reporter lines for visualizing Tregs, as well as transgenic lines for targeted genetic manipulation and specific depletion of these cells. Such models are essential for deepening our understanding of Treg function and significance in different immunological contexts.
In their Science 2025 publication (Jobin et al.), the research groups of Wolfgang Kastenmüller and Georg Gasteiger investigated the function of Tregs during an antiviral immune response. Tregs suppress other immune cells, such as CD8⁺ T cells, by competing for IL-2 derived from CD4⁺ helper T cells.
The groups also study how Tregs develop in various tissues and what roles the individual subpopulations of these cells play, in order to better understand how Tregs act within the body.
Tissue-Resident Tregs in Organs
Almost all organs host tissue-resident lymphocytes, including Tregs, which play a front-line role in immune surveillance. Tregs interact with other immune and tissue cells, promote tissue homeostasis, and support repair processes. Their strategic positioning across different organs makes them crucial for maintaining the balance between effective defense, tissue integrity, and the control of inflammation or autoimmune reactions.
The group led by Georg Gasteiger, head of the Max Planck Research Group, investigates how local lymphocyte networks form in various tissues, how Tregs interact with other immune cells, and which organ-specific functions they perform – both under physiological conditions and during infections or inflammation.
Regulatory T Cells in the Gut
The group led by Jakob Zimmermann at the Institute of Systems Immunology, University of Würzburg, studies how T cells and the gut microbiome cooperate and what role they play in chronic inflammatory diseases. Regulatory T cells are of particular importance, as they suppress inflammation and maintain immune balance in the gut.
Research has shown that these T cells emerge around the time of weaning, when the microbiota diversifies significantly due to dietary changes. These early regulatory T cells are crucial for preventing microbiota-driven immune pathologies later in life.
“We study how bacteria within the complex gut microbiota influence the differentiation of T cell subtypes - some of which are pro-inflammatory, while others, like the Nobel Prize–recognized regulatory T cells, are anti-inflammatory. We focus on bacterial dose, duration of exposure, diet, and the maturity of the immune system,” explains the group leader. “The function of Tregs depends in part on inhibitory molecules such as CTLA-4, whose importance I had the privilege of hearing about firsthand from Shimon Sakaguchi at the DGfI Annual Meeting in Hanover in 2022.”
The goal of the Zimmermann Lab is to enhance the induction of regulatory T cells in order to prevent chronic inflammatory bowel diseases. The team investigates how their lifespan is influenced by the immune system and the microbiota, and how this knowledge can be leveraged for therapeutic approaches.
Treg Research by Our Scientists
M. Vaeth et al. Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1), Proc. Natl. Acad. Sci. U.S.A. 108 (6) 2480-2485, https://doi.org/10.1073/pnas.1009463108 (2011).
M. Vaeth et al. Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3+ regulatory T cells, Proc. Natl. Acad. Sci. U.S.A. 109 (40) 16258-16263, https://doi.org/10.1073/pnas.1203870109 (2012).
Martin Vaeth et al. Follicular regulatory T cells control humoral autoimmunity via NFAT2-regulated CXCR5 expression. J Exp Med (2014) 211 (3): 545–561. https://doi.org/10.1084/jem.20130604
Vaeth, M., Wang, YH., Eckstein, M. et al. Tissue resident and follicular Treg cell differentiation is regulated by CRAC channels. Nat Commun 10, 1183 (2019). https://doi.org/10.1038/s41467-019-08959-8
Katarzyna Jobin et al, A distinct priming phase regulates CD8 T cell immunity by orchestrating paracrine IL-2signals. Science388, eadq1405(2025). DOI:10.1126/science.adq1405
Kaminski A, Hager FT, Kopplin L, Ticconi F, Leufgen A, Vendelova E, Rüttger L, Gasteiger G, Cerovic V, Kastenmüller W, Pabst O, Ugur M. Resident regulatory T cells reflect the immune history of individual lymph nodes. Sci Immunol. 2023 Nov 24;8(89):eadj5789. doi: 10.1126/sciimmunol.adj5789
