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Nobel Prize in Physiology or Medicine 2025: The checks and balances in the immune system
Nobel Prize in Physiology or Medicine 2025: The checks and balances in the immune system

Nobel Prize in Physiology or Medicine 2025: Tregs – The checks and balances in the immune system

6’
Immunology

Celebration is in the air! Let’s look into the winners of the latest Nobel Prize in Physiology or Medicine, and their discovery: the Tregs.

Who won the 2025 Nobel Prize in Physiology or Medicine?

The Nobel Assembly has awarded the 2025 Nobel Prize in Physiology or Medicine to three scientists “for their discoveries concerning peripheral immune tolerance.”

  • Mary E. Brunkow, Institute for Systems Biology, Seattle, USA
  • Fred Ramsdell, Sonoma Biotherapeutics, San Francisco, USA
  • Shimon Sakaguchi, Osaka University, Osaka, Japan

Their work revealed how specialized immune cells called regulatory T cells (Tregs) act as the body’s “security guards,” preventing the immune system from attacking our own cells.

These discoveries explained why most of us do not develop catastrophic autoimmunity, and have inspired new therapies for cancer, autoimmunity, and transplantation by modulating Tregs activities.

Most of us are familiar with Tregs, but it is really interesting to back at how these essential cells were discovered—and how much we still don’t understand.

What are Tregs and how were they discovered?

Regulatory T cells (Tregs) are specialized CD4+ T cells that suppress excessive or misdirected immune responses.  

  • Sakaguchi et al. (1995) first identified CD4+CD25+ T cells in mice. Depleting these cells in mouse models resulted in severe autoimmune disease, demonstrating their role in regulating immune responses.
  • Mary Brunkow and Fed Ramsdell (Bennett  et al., 2001; Wildin et al., 2001) subsequently identified a master transcription factor, Foxp3. Foxp3 mutations in humans cause IPEX, a severe multi-organ autoimmunity syndrome. They had to sequence a portion of the X chromosome and screen 20 genes one by one, all before NGS technology became available.
  • Sakaguchi and colleagues established that FOXP3 controls Treg development (Hori et al. 2003, Science) ; see also a historical overview and mechanistic summary in Sakaguchi et al. (2007).

Why are Tregs important

  • Autoimmunity: The early focus was on Tregs’ role in self-tolerance. FOXP3 dysfunction in humans (IPEX) demonstrates that Tregs are indispensable for preventing autoimmunity (Wildin et al., 2001). Ongoing trials aim to expand or transfer Tregs to treat autoimmune diseases such as type 1 diabetes, lupus, and Crohn’s disease (Goswami et al., 2022).
  • Transplantation and inflammation: Strategies that expand or reinfuse Tregs are being explored to reduce graft-versus-host disease (GVHD) and rejection; For example, allogenic transfer of Tregs is under clinical evaluation (Lysandrou, et al., 2025)
  • Cancer biology: Many tumors accumulate Tregs, which can dampen anti-tumor immunity; suppressing Treg’s protective function is an active area in immuno-oncology. For example, Luo et al. (2024) identified effector Tregs (eTregs) to be a potential target in ovarian cancer treatment.

Beyond CD25 and FOXP3

Since the initial characterization of Tregs, scientists have observed wide heterogeneity in Tregs in suppressive capacity, surface marker expression, cytokine profiles, and tissue localization.

The discovery is further accelerated by single cell sequencing, which enabled unbiased discovery of whole transcriptome profiles. It revealed continuous differentiation states rather than discrete subsets—Tregs exist along transcriptional gradients reflecting activation status, tissue adaptation, and functional specialization (Luo et al. 2021).

Single cell sequencing also revealed Tregs dynamics: Upon stimulation, Tregs subpopulations may maintain or loss their FOXP3 expression, and therefore take on immune suppressive or effector phenotypes (Yi et al. 2020).

Single Cell TCR Sequencing: Tracking Clones and Antigen Specificity

While scRNA-seq reveals transcriptional states, scTCR-seq adds another critical dimension: clonal relationships and antigen recognition patterns. By reconstructing paired TCR alpha and beta chains from single cells, researchers can track which Treg clones expand in response to specific challenges.

Luo et al. (2024) used sCircle single cell full-length TCR sequencing to trace clonal evolution of Treg subsets and suggested that potentially tissue-resident Tregs are replenished from the peripheral circulation.

Deep dive into Treg clonality: Learn more about sCircle

Technical advances enable retrospective analysis:

  • Methods now exist to recover full-length TCR sequences from standard 3′ scRNA-seq libraries (for example, with sCircle technology)
  • Specialized tools like scRepertoire integrate TCR data with transcriptomics for comprehensive analysis

The major limitation? Determining antigen specificity from TCR sequence alone remains challenging, though machine learning approaches are improving predictions. Expanded databases linking Treg TCR sequences to self-antigens would transform our ability to engineer antigen-specific Tregs for therapy.

Key Takeaways for Researchers

  • Tregs are far more heterogeneous than FOXP3 expression suggests, with continuous differentiation states and specialized subsets
  • Disease-associated transcriptional changes often involve loss of stability, metabolic reprogramming, or acquisition of pathogenic features
  • Tissue-specific adaptation programs are conserved across species and contexts, offering universal therapeutic targets
  • Clonal dynamics differ dramatically between disease contexts—recruitment vs. expansion patterns inform therapeutic strategies

What remains to be solved:

  • Definitively distinguishing thymic-derived from peripherally-induced Tregs
  • Mapping comprehensive antigen specificities for Treg TCR repertoires
  • Understanding precise mechanisms governing stability and plasticity
  • Translating single-cell insights into effective clinical interventions with long-term persistence

Practical considerations:

  • Single cell profiling is becoming more accessible and cost-effective
  • Standardized computational pipelines and reference atlases enable cross-study comparisons
  • Integration with functional validation remains essential—descriptive profiling must connect to mechanism
  • Longitudinal sampling to track dynamics over time is logistically challenging but highly informative

References

  • Bennett, C. L., Christie, J., Ramsdell, F., et al. (2001). The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genetics, 27(1), 20–21. https://doi.org/10.1038/83713
  • Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., et al. (2001). Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genetics, 27(1), 68–73. https://doi.org/10.1038/83784
  • Goswami, T. K., Singh, M, Dhawan, M., et al. (2022). Regulatory T cells (Tregs) and their therapeutic potential against autoimmune disorders: Advances and challenges. Human Vaccines & Immunotherapeutics, 18(1), 2035117. https://doi.org/10.1080/21645515.2022.2035117
  • Hori, S., Nomura, T., Sakaguchi, S. (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science, 299(5609):1057-61. https://doi.org/10.1126/science.1079490
  • Luo, Y., Xu, C., Wang, B. et al. (2021). Single-cell transcriptomic analysis reveals disparate effector differentiation pathways in human Treg compartment. Nat Commun 12, 3913. https://doi.org/10.1038/s41467-021-24213-6
  • Luo, Y., Xia, Y., Liu, D., et al. (2024). Neoadjuvant PARPi or chemotherapy in ovarian cancer informs targeting effector Treg cells for homologous-recombination-deficient tumors. Cell, 187(18), 4905–4925.e24. https://doi.org/10.1016/j.cell.2024.06.013
  • Nobel Prize. (2025). The Nobel Prize in Physiology or Medicine 2025: Press release. https://www.nobelprize.org/prizes/medicine/2025/press-release/
  • Nobel Prize. (2025). Popular information: The Nobel Prize in Physiology or Medicine 2025. https://www.nobelprize.org/prizes/medicine/2025/popular-information/
  • Sakaguchi, S., Sakaguchi, N., Asano, M., et al. (1995). Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25): Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. Journal of Immunology, 155(3), 1151–1164. https://pubmed.ncbi.nlm.nih.gov/7636184/
  • Sakaguchi, S., Wing, K., & Miyara, M. (2007). Regulatory T cells—A brief history and perspective. European Journal of Immunology, 37(S1), S116–S123. https://pubmed.ncbi.nlm.nih.gov/17972345/
  • Wildin, R. S., Ramsdell, F., Peake, J., et al. (2001). X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nature Genetics, 27(1), 18–20. https://doi.org/10.1038/83707
  • Yi, G., Zhao, Y., Xie, F., et al. (2020). Single-cell RNA-seq unveils critical regulators of human FOXP3+ regulatory T cell stability. Science Bulletin, 65(13), 1114-1124, https://doi.org/10.1016/j.scib.2020.01.002
A post by Yingting Wang

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