Assistant Professor University of Massachusetts Chan Medical School Worcester, Massachusetts, United States
Disclosure(s):
Michela Frascoli, PhD: No financial relationships to disclose
Introduction/Rationale: 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.
Methods: 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.
Results: 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 T (T17) cells. These cells also express the CBF-RUNX complex consistent with a pioneer/lineage-competence role. Using mice carrying a mutation in the CBF2 isoform, previously shown to be essential for T cell development, we demonstrate that CBF2 haploinsufficiency rewires transcriptional regulatory circuits in adult bone marrow progenitors, rendering them permissive for an early life-restricted T17 cells.
Conclusion: Together, these data provide a reference framework for fetal hematopoiesis and reveal how embryonic gene-regulatory programs encode the foundations of layered immunity.
