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Nobel Prize T-Regs: FOXP3 & Immune Control

54:02 recording · AUTO · 3 speakers

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Brief overview

The 2025 Nobel honours regulatory T cells, and FOXP3 is the marker that finally defined them.

  1. FOXP3 defines the Treg, CD25 never couldCD25 is also switched on by any recently activated T cell, so only the FOXP3 transcription factor gave the field a specific identity for these cells.
  2. A transcription factor is a hard marker to work withTo see FOXP3 you must lyse, fix or stain the cell, which destroys the function you wanted to test, so the team used a GFP-FOXP3 retrovirus and later lineage tracing instead.
  3. Discarded ideas can come back renamedSuppressor T cells were ridiculed after the IJ gene collapsed, and returned decades later as regulatory T cells with a Nobel attached.
Executive Summary AI
  • Vincent Racaniello, Cindy Leifer and Brianne Barker open Immune 99 on the Nobel Prize in physiology or medicine to Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi for regulatory T cells, which are CD4 positive, CD25 positive and FOXP3 positive.1:56
  • They trace the messy history first: Richard Gershon published on suppressor T cells as early as 1970, the supporting IJ gene turned out not to exist, and Barker was taught as a student that suppressor and danger were words no real immunologist would ever say, until the field quietly rebranded suppression as regulation.3:55
  • Sakaguchi's 1995 Journal of Immunology paper, later chosen as a pillars-in-immunology paper and republished in April 2011, showed that adding back CD4 positive CD25 positive T cells prevented autoimmunity in thymectomized animals, but CD25 is the IL-2 receptor alpha chain and also appears on recently activated T cells, so it was never a specific marker.10:55
  • Brunkow and Ramsdell at Celltech Kairoscience sequenced the scurfy mouse and found a two base pair insertion creating a stop codon in forkhead box P3, and the same gene is mutated in boys with IPEX, an X-linked disease whose autoimmune symptoms kill most of them in the first few years of life.17:11
  • The paper discussed, Hori, Nomura and Sakaguchi in Science, February 2003, used retroviral transfer of FOXP3 with GFP to show FOXP3 mRNA is 100-fold more abundant in CD25 positive CD4 cells, that forced FOXP3 turns naive T cells into contact-dependent suppressors, and that those cells block colitis and gastritis in mice.22:12
Key Quote
“The word suppressor still kind of went away.”
— Cindy Leifer8:11
Key Quote
“Unfortunately, Richard Gershon died at 50 and he never got to see any of this, right?”
— Vincent Racaniello8:35
Key Quote
“And just further emphasizing the serendipity of science that I wish people would understand more that you got to let scientists just be curious, right, and good things will happen.”
— Vincent Racaniello29:10