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Last week we looked at Juan Lafaille's demonstration of T cell regulation in the EAE system. Now here's another side of Treg history- it starts, of course with an experimentally well founded hypothesis about the thymus controlling sex organ development.
Back in the 60s, the idea that the thymus (gland) was an important part of the endocrine system was alive and well- even if the work of Jacques Miller, Robert Good & Max Cooper among others had already made its importance to lymphocyte biology clear.
Nishizuka and Sakakura described in Science in 1969 the very reproducible phenomenon that in some strains of mice, neonatal thymectomy led to severy atrophy of the gonads. https://science.sciencemag.org/content/166/3906/753.abstract
Because the immunologic role of the thymus was known, they checked lymphocyte numbers and immune function, and found both to be normal or close to normal. So they considered it more likely gonadal atrophy due to thymectomy was not due to immune dysfunction.
Soon it became clear to Nishizuka & Sakakura that lymphocyte infiltration was a characteristic of the gonads of neonatally thymectomized mice (in the original report they considered that the atrophy might be linked to a viral infection). https://academic.oup.com/endo/article-abstract/89/3/886/2620806
By the beginning of the '80s, it had become clear that, in a strain- & timing-dependent manner, neonatal thymectomy led to a series of organ specific experimental autoimmune diseases https://pubmed.ncbi.nlm.nih.gov/7039891/
This is when Shimon Sakaguchi enters the story, initially working with Yashuaki Nishizuka to characterize the cells responsible for the autoimmunity in a series of adoptive transfer experiments
https://rupress.org/jem/article/156/6/1565/49046/Study-on-cellular-events-in-postthymectomy?searchresult=1
https://rupress.org/jem/article/156/6/1565/49046/Study-on-cellular-events-in-postthymectomy?searchresult=1
The major shift is when Sakaguchi stops focusing on pathogenic autoreactive T cells, and begins looking for protective regulatory T cells (as you can see below, he was using the term in 1982)
https://rupress.org/jem/article/156/6/1577/49055/Study-on-cellular-events-in-post-thymectomy?searchresult=1
https://rupress.org/jem/article/156/6/1577/49055/Study-on-cellular-events-in-post-thymectomy?searchresult=1
For well over a decade, he and his collaborators tried to find a reliable, reproducible marker for this population, until in 1995, he introduced CD25 as a Treg marker to the world https://www.jimmunol.org/content/155/3/1151.short
Almost a decade after that, together with my former lab & flatmate Shohei Hori, Sakaguchi found that the transcription factor Foxp3 controlled the development of the Treg lineage. https://science.sciencemag.org/content/299/5609/1057.abstract?casa_token=2Etr32StzicAAAAA:88OK8CmJhF76tEqXM9iyy720tdFG1TJdPpGaEtAnw3btUHRivYvDQgs9Aes4WoSk6DlxI4EbL2IBRY8
The role of Foxp3 in Treg development was reported at the same time by Jason Fontenot & Sasha Rudensky based on analysis of a spontaneous foxp3 mutant mouse line, the scurfy mice https://www.nature.com/articles/ni904
and also by Rolli Khattri & Fred Ramsdell- which sometimes mess with search engines because they refer to Foxp3 as "Scurfin" https://www.nature.com/articles/ni909
