In-Utero Imprinting of Gene Regulatory Networks Underpinning Innate-Like T Cell Development 2260347

Abstract

The mammalian immune system develops through a layered process in which successive waves of embryonic hematopoiesis give rise to distinct progenitors that seed and sustain the neonatal and adult immune compartments. The tissue-based early immune system prioritizes barrier protection by constraining inflammation, whereas the adult immune system is optimized for durable pathogen control and memory. To define the heterogeneity of embryonic precursors that differentiate into immune subsets emerging early in life, we generated a high-resolution single-cell transcriptomic atlas of mouse embryonic hematopoiesis spanning E8.5-E15.5 at 12-hour intervals, encompassing yolk sac, para-aortic-splanchnopleura/aorta-gonad-mesonephros (PsP/AGM), and fetal liver. The atlas resolved canonical myeloid (including tissue-resident macrophages), lymphoid (including ILC progenitors), and stromal lineages. Moreover, it revealed previously uncharacterized progenitors biased toward innate-like and tissue-resident lymphoid fates. Notably, we identify precursors bearing a Sox13, Atv5, Tcf7, Notch1, Myb and Lef1 gene regulatory module that imposes effector identity to IL-17 secreting γδ T (Tγδ17) cells. These cells also express the CBFβ2-RUNX complex consistent with a pioneer/lineage-competence role. Using mice carrying a mutation in the CBFβ2 isoform, previously shown to be essential for γδ T cell development, we demonstrate that CBFβ2 haploinsufficiency rewires transcriptional regulatory circuits in adult bone marrow progenitors, rendering them permissive for an early life-restricted Tγδ17 cells. Together, these data provide a reference framework for fetal hematopoiesis and reveal how embryonic gene-regulatory programs encode the foundations of layered immunity. n/a Hematopoiesis and Immune System Development (HEM)