A wave of bipotent T/ILC-restricted progenitors shapes the embryonic thymus microenvironment in a time-dependent manner.

During embryonic development, multiple waves of hematopoietic progenitors with distinct lineage potential are differentially regulated in time and space. Two different waves of thymic progenitors colonize the fetal thymus where they contribute to thymic organogenesis and homeostasis. The origin, the lineage differentiation potential of the first wave and their relative contribution in shaping the thymus architecture, remained, however, unclear. Here we show that the first wave of thymic progenitors comprises a unique population of bipotent cells generating lymphoid tissue inducer, in addition to invariant Vg5+ T cells. Transcriptional analysis revealed that innate lymphoid gene signatures and more precisely the lymphoid tissue inducer associated transcripts were expressed in the first but not in the second wave of thymic progenitors. Depletion of early thymic progenitors in a temporally-controlled manner showed that the progeny of the first wave is indispensable for the differentiation of autoimmune regulator expressing medullary thymic epithelial cells. We further show that these progenitors are of strict hematopoietic stem cell origin, despite the overlap between lymphopoiesis initiation and the transient expression of lymphoid associated transcripts in yolk sac erythro-myeloid restricted precursors. Our work highlights the relevance of the developmental timing on the emergence of different lymphoid subsets, required for the establishment of a functionally diverse immune system.

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