T-rific News: T cells Just Won a Nobel!

14 Oct, 2025

• The 2025 Nobel prize in Medicine was awarded to Shimon Sakaguchi, Mary E.Brunkow, and Fred Ramsdell for their discoveries about peripheral immune tolerance.
• Their work centers on a specialized subset of T cells known as regulatory T cells (Tregs), which act as a kind of immune “ brake” to prevent the immune system from attacking the body’s own tissues.
• These discoveries greatly improved our understanding of peripheral immune tolerance - how the immune system is kept in check and how breakdowns of that system can lead to autoimmunity.

Timeline of discoveries

• In 1995, Sakaguchi and his colleagues discovered a new population of T-cells that had suppressive functions and could prevent autoimmunity.
  • They removed an organ called the Thymus from mice and saw that the mice almost immediately died from extreme autoimmunity, which puzzled them.
• In 2001, Brunkow and Ramsdell discovered a gene named Foxp3, that when mutated in mice lead to a lethal autoimmune syndrome.
• Later, Sakaguchi and others showed that Foxp3 is a master regulator for Treg development and function, linking the suppressive cells to that gene.

How do T-cells work?

• T-cells are a class of lymphocytes (white blood cells) that develop from progenitors in the bone marrow but mature in the Thymus (”T” for thymus :) )
• There are different types of T-cells
  • CD8+ “cytotoxic” T cells can kill infected cells or tumour cells.
  • CD4+ “ helper” T cells help in providing signals to B cells, macrophages and other immune cells.
• T cells become activated after binding to the antigen presented on the surface of Antigen Presenting Cells, via MHC (Major Histocompatibility Complex) molecules, which are molecules that carry the peptide fragment to the cell surface.

Self-tolerance and elimination of self-reactive T cells

• Some T cells will have receptors that recognize self antigen. If these escape regulation, they could attack the body’s own tissues.
• Central tolerance: T cells are screened as they develop in the thymus. Strongly self-reactive T cells are eliminated. This removes many dangerous T cells before they exit into circulation.
  • This is often how autoimmune diseases work, because helper T cells may help B cells produce autoantibodies, or other T cell subsets can produce proinflammatory cytokines that worsen pathology.
  • Turns out that in Sakaguchi's earlier experiments, removing the thymus removed the body's ability to screen and delete the over reactive T cells, leading to autoimmunity.
• But central tolerance is not perfect, and some self-reactive T cells do escape into peripheral tissues. This is where peripheral tolerance mechanisms come in to suppress or eliminate those cells.

Regulatory T cells (Tregs): the “brakes” of immunity

• Regulatory T cells are a subset of CD4+ T cells specialized to suppress or limit immune responses, especially self-reactive one.
• Sakaguchi in 1995 showed that injecting these T cells into neonatal mice could prevent them from developing autoimmune disease, indicating that some T cells have suppressive function.
• Later studies done by Brunkow & Ramsdell discovered that mutation of Foxp3 in mice caused a lethal autoimmune disease and Sakaguchi’s group read this study and showed that Foxp3 is a transcription factor, essential for the development, stability and suppressive function of Tregs. Eureka!

Mechanisms of suppression by Tregs

• Cytokine-mediated suppression
• Metabolic disruption: consuming IL-2, depriving effector T cells
• Cytolysis: killing other immune cells
• Modulating antigen-presenting cells (APCs) to reduce their activation of effector T cells
• Inhibitory receptors/molecules: CTLA-4 expression to down regulate costimulatory molecules on APCs

Treatments

• Treg expansion/adoptive transfer
  • One approach is to isolate a patient’s own Tregs, expand them ex vivo, and infuse them back to suppress autoimmunity or prevent transplant rejection.
  • Another is to engineer antigen-specific Tregs (for example, Tregs that recognize a specific autoantigen) for more targeted suppression.
• Enhancing Treg function in vivo
  • Using drugs or biologics that boost Treg numbers, stability or suppressive capacity.
  • Targeting molecules that stabilize Foxp3 expresssion
  • Modulating pathways that inhibit Treg suppression
• Gene therapy/genetic correction
  • For cases of Foxp3 mutation, gene therapy might repair or replace the defective gene in Treg precursors.
  • More broadly, gene editing might be used to reprogram conventional T cells into suppressive Tregs.
• Combiantion immunomodulation
  • Using Treg-based strategies alongside other immunomodulatory treatments to tip the balance toward tolerance without global immunosuppression.