Human unconventional T cell development is programmed in the thymus 3484

Description Unconventional T cells represent more than 10% of total T cells within the blood and tissues of humans and play critical roles in cancer and infection. Unconventional T cells include Mucosal invariant T (MAIT) cells, gamma delta T cells and Natural Killer T (NKT) cells. We have previously showed that MAIT cells and Vd2+ T cells develop via a three-stage linear pathway within the human thymus. Here, we define the thymic development of human NKT cells, identifying a four-stage pathway involving the upregulation of transcription factor PLZF and the Killer cell lectin-like receptor subfamily B, member 1 (CD161). We also define the epigenetic changes that govern the development of human MAIT cells. Finally, we demonstrate that three-stage thymic development pathway defined for human Vd2+ T cells can be faithfully reproduced using artificial thymus organoids, allowing for detailed interrogation of this process. Collectively, our work sheds important new light on human unconventional T development and may lead to new opportunities to influence the development of these cells to treat human disease. Funding Sources DGP was previously supported by the CSL Centenary Fellowship (2019-2023) and is now supported by the Sylvia & Charles Viertel Fellowship. This research is supported by NHMRC grant (2030186).