How does the thymus prevent or predestine autoimmune disease?

To be able to stave off infections and cancers throughout life, our immune systems first need to recognise and tolerate the ~200 different cell types in healthy human bodies ('self'). Reflecting its oppositeness from well-known responses in which immune cells are (positively) selected, this response is called 'negative selection'. For T cells, negative selection occurs during development in the thymus. Researchers have analysed negative selection of certain T cells, but the field has been frustrated by the lack of a molecular marker that identifies all cells undergoing negative selection. Our 2013 Journal of Experimental Medicine paper described just such a marker, Helios. This innovation allows any researcher to analyse T cells undergoing negative selection in mice or humans. In both species, we have found evidence for 2 "waves" of T cell negative selection in the thymus. The first "wave" occurs early in development, when the T cells are probably located in the cortex of the thymus. We think this "wave" eliminates T cells with receptors that bind strongly to one or more self-antigens. The second "wave" occurs later in development when the T cells are located in the medulla of the thymus. This "wave" also involves T cells with receptors that bind strongly to self-antigen. Why, then, did these cells fail to get eliminated in the first wave? We think the answer is because different sets of self-antigens are presented to T cells in the cortex versus the medulla of the thymus. Some T cells in the second wave survive, and up-regulate expression of a transcription factor called Foxp3, which cripples their inflammatory potential. These Foxp3-expressing T cells dampen self-destructive immune responses. Autoimmune diseases may originate from defects in Foxp3-expressing T cells. Our research aims to understand the separate but complementary functions of the 2 "waves" of T cell negative selection in the thymus, and how autoimmune diseases may originate with failure of one or both "waves".