LAUSR

Autoimmune disorders (ADs) arise from deregulated self-reactive immune response. Currently, little is known about ADs’ pathogenesis. To investigate the cell of origin of ADs, we exploited the context of Omenn Syndrome (OS), a genetic disease due to hypomorphic mutations in genes involved in V(d)J recombination. This leads to the paradigmatic coexistence of immunodeficiency and autoimmunity, offering the unparalleled platform to study AD onset in absence of the adaptive immune system. In OS patients, the autoreactive T-cells triggering trigger the typical autoimmune inflammation in the skin and intestine show a highly conserved and restricted TCR usage. This and other peculiar features of OS T-cells closely resemble those of the first lymphocytes emerging before and independently from hematopoietic stem cells (HSCs). Therefore, we speculated that OS autoreactive T-cells are mostly generated in the embryo independently from HSCs. To address this hypothesis, we isolated E9.5 embryonic hematopoietic progenitors as well as adult HSCs from both wild-type (wt) and the RAG2R229Q OS mice and analyzed their T-lymphoid potential. While both wt E9.5 cells and adult HSCs can differentiate in CD3+ T-cells in vitro, only embryonic progenitors can generate CD3+ cells in OS setting. Of note, fetal reprogramming of OS adult HSCs by Lin28 ectopic expression rescued their lymphoid potential. Similarly, differentiation of patient-derived induced pluripotent stem cells shows that human embryonic lymphoid progenitors with OS mutations can generate CD3+ cells, thus supporting our hypothesis. Our studies describe the previously unappreciated contribution of embryonic progenitors to the pool of autoimmune lymphocytes, providing a platform for both the detailed study of human AD and the design of more targeted therapies.