From Nobel recognition to therapeutics screening: the Treg revolution.

The prestigious 2025 Nobel Prize in Physiology or Medicine celebrates the outstanding contributions of Mary E. Brunkow, Frederick J. Ramsdell, and Shimon Sakaguchi for their remarkable breakthroughs in understanding peripheral immune tolerance through regulatory T cells. Their pioneering work underscores the vital role these cells play in maintaining immune system balance.

Notably, Sakaguchi's discovery of regulatory T cells in 1995, along with their significant link to the Foxp3 gene identified in 2003, has significantly advanced the field. Furthermore, Mary E. Brunkow and Fred Ramsdell’s identification of Foxp3 mutations associated with autoimmune diseases in mice and humans in 2001 highlights the profound impact of their research on health and medicine.

What are regulatory T cells?

Regulatory T cells (Tregs) are a specific subgroup of CD4+ T cells essential for maintaining immune balance. Their primary role is to suppress or "regulate" immune responses, preventing the immune system from attacking the body's own tissues. This process, called peripheral immune tolerance, is vital for avoiding autoimmune diseases.

Revolutionary implications for drug discovery

Tregs suppress excessive immune responses to maintain tolerance and prevent autoimmunity. In immunotherapy, especially for cancer, Tregs hinder anti-tumor immunity by inhibiting effector T cells, so strategies like depletion or inhibition enhance treatment efficacy. Consequently, Tregs have fundamentally transformed the landscape for drug discovery, opening up several groundbreaking therapeutic avenues. These breakthroughs have considerable implications across multiple disease areas, notably:

Autoimmune disease: The concept that Tregs maintain self-tolerance has established a completely new approach for treating autoimmune diseases. Therapeutic developers can:

• Focus on therapies that specifically boost Treg function or stability in conditions such as rheumatoid arthritis, multiple sclerosis, type 1 diabetes, and inflammatory bowel disease.
• Design small molecules that encourage Treg expansion or enhance their suppressive ability.
• Develop biologics that target specific Treg signaling pathways without impairing overall immunity.
• Investigate cell therapy methods using ex vivo expanded autologous Tregs.

Cancer Immunotherapy: In oncology, recognizing that tumors often exploit Tregs to evade immune surveillance has led to:

• Development of selective Treg-depleting agents that preserve effector T cell function.
• Combination therapies that target Tregs and other immune checkpoints simultaneously.
• Biomarker strategies using Treg signatures to predict responses to immunotherapy.
• Innovative approaches to reprogram the tumor microenvironment by modulating Treg activity.

Transplantation Medicine: In organ transplantation, Treg biology provides:

• The potential to induce donor-specific tolerance without the need for broad immunosuppression.
• Cellular therapies using expanded recipient Tregs to prevent graft rejection.
• Pharmacological strategies to promote Treg-mediated tolerance at the transplant site.
• A decreased reliance on lifelong immunosuppressive drugs and their associated side effects.

The Treg revolution

These Nobel-winning discoveries have fundamentally transformed immune modulation strategies, shifting from broad immunosuppression to precision targeting of specific T cell subsets, pathway-specific interventions, personalized therapies based on individual Treg profiles, and companion diagnostics to identify optimal responders. The pharmaceutical industry has responded enthusiastically with multiple clinical-stage programs, significant investments in Treg-focused biotechs, and academia-industry partnerships translating basic science into therapies.

Despite promising advances, challenges persist in achieving selective Treg modulation without affecting conventional T cells, maintaining long-term stability, and developing tissue-specific targeting strategies. Revvity's specialized assay platforms provided through its preclinical services address these challenges by enabling efficient compound screening for Treg-specific effects, mechanism characterization, and therapeutic potential assessment before moving to costly in vivo studies—accelerating development of next-generation immunomodulatory therapies that could transform treatment paradigms across multiple diseases.

Key characteristics of Tregs include:

• Expression of specific markers: CD25 (IL-2 receptor) high, CD127 (IL-7 receptor) low, and most importantly, the transcription factor Foxp3, which is considered the lineage-defining marker for Tregs.
• Production of anti-inflammatory cytokines such as TGF-β and IL-10.
• Ability to suppress the activation and proliferation of other immune cells through various mechanisms, including direct cell-to-cell interactions.
• Expression of immune checkpoint molecules like CTLA4, LAG3, and PD-1.
• Tregs exist in two primary forms: naturally occurring Tregs (nTregs) that develop in the thymus, and induced Tregs (iTregs) that can be generated from naïve CD4+ T cells under specific conditions.

Revvity’s preclinical services research solutions in Treg

Treg polarization assay

Our semi-automated platform for Treg polarization assays transforms naïve CD4+ T cells into induced regulatory T cells (iTregs) with high consistency across donors. It features 384-well high-throughput screening formats, comprehensive marker analysis (Foxp3, CD25, CD127, PD-1), essentially designed for compound testing capabilities, and the potential for CRISPR-based gene function assessment.

This flexible system speeds up the development of new therapeutics for autoimmune diseases (by improving Treg function) and cancer immunotherapies (by suppressing Treg function), offering valuable insights into compounds that influence Treg development and activity.