Although it is not the focus of my research, the establishment of thymic (central) tolerance has been for me one of the most puzzling aspects of T cell development. In the mid-1990s, as I started my postdoc, the conventional view was that thymic tolerance was mediated by negative selection (deletion) of self-reactive cells, with much experimental support from results gathered in previous years. But how could all or most self-reactive thymocytes be deleted, given the limited time that they spend in the thymus and the multiplicity of self-antigens? Neonatal thymectomy experiments had suggested another mechanism of tolerance, through the generation of ‘regulatory’ T cells with suppressive activity, but the relationship between these putative cells and thymic selection was unclear.

A major step forward came in 1995 with the identification by Shimon Sakaguchi and colleagues of CD25 as a marker for such regulatory T (Treg) cells. This was followed by the findings that Treg cells are indeed of thymic origin and that their absence accounts for the autoimmune disease that arises after neonatal thymectomy in mice. Thus, there was another mechanism for thymic tolerance. The question became whether it was related to self-reactivity.

A paper by Jordan et al. published in 2001 gave a crucial clue to the answer. The key findings of this elegant study were that CD25+ Treg cells can be selected on self-peptides and that their development requires high-affinity interactions between the T cell receptor and antigen. Thus, the emerging idea, validated by subsequent studies, was that self-reactive thymocytes could not only be deleted (negative selection) but also diverted to an immunosuppressive fate and therefore contribute to tolerance in trans.

Together with the demonstration of widespread expression of tissue-specific antigens by medullary thymic epithelial cells (Derbinski et al., 2001), the paper by Jordan et al. provided important insights into T cell tolerance. But the story is far from over. Although subsequent studies deciphered the mechanisms of both Treg cell differentiation and tissue-specific antigen expression in the thymus, much remains to be understood as to what directs thymocytes towards deletion or conventional versus regulatory T cell differentiation.