The discovery of regulatory T (Treg) cells has transformed immunology. In the pre-Treg cell era, our concept of immune tolerance was that it largely involved a developmental purge of autoreactivity. Today, we understand that immune tolerance is a dynamic and ongoing process.

Evidence for tolerogenic T cells dates back nearly 50 years. Unfortunately for the field, many of the early insights were tossed away together with the suppressor T cell model in the 1980s, a concept that collapsed under the weight of experimental artifacts. It took the labour of Shimon Sakaguchi and Fiona Powrie in the 1990s to bring Treg cells back into a sceptical field; the concept did not gain full acceptance until landmark publications in 2003 from the labs of Sakaguchi, Alexander Rudensky and Fred Ramsdell that linked forkhead box protein P3 (FOXP3) expression to Treg cell differentiation and function. Here, I would like to highlight a forgotten gem of the 1980s — two studies by Nicole Le Douarin and colleagues.

These landmark papers in 1987 and 1988 used an elegant microsurgical system of grafting the wing buds of quail onto embryonic chickens. The grafted quail wing bud would grow into a normal quail wing as the chick developed, but was quickly rejected after hatching. If, however, proto-thymus from the same quail was simultaneously grafted into the chick embryo, the adult chicken could survive for months with intact quail wings. These results clearly demonstrated the power of the thymic epithelium to induce cross-species tolerance in the developing T cells, even if only part of the thymic epithelium was of quail origin. The chick–quail marker system that had earlier been developed by Le Douarin, together with the unique structure of the chicken thymus, with 10–16 anatomically separated thymic lobes, was used to prove dominant tolerance: chicken T cells that developed in a chicken thymic lobe could be controlled by chicken T cells that developed in a quail thymic lobe.

These papers are a must read for students starting a career in Treg cells. They show the virtue of patience in tool development and of understanding developmental biology. The studies showed the existence of a key cell type that took another 15 years to conclusively identify, and Le Douarin did so at a time when the work of many of her colleagues was sinking into the quagmire of the putative I–J suppressor region of the MHC.