Abstract The human fetal immune system starts to develop in the first trimester and likely plays a crucial role in fetal development and maternal-fetal tolerance. Innate lymphoid cells (ILCs) are the earliest lymphoid cells to arise in the human fetus. ILCs consists of natural killer (NK) cells, ILC1s, ILC2s, and ILC3s that all share a common lymphoid origin. Here, we studied fetal ILC subsets, mainly NK cells and ILC3s and their potential progenitors, across human fetal tissues from the first and second trimesters. Our results show that fetal ILC subsets have distinct distribution, developmental kinetics, and gene expression profiles across human fetal tissues. Furthermore, we identify a putative CD34 + RORγt + Eomes +/− ILC progenitor population exclusively present in fetal intestine, indicating that tissue-restricted development of ILCs could contribute to the variation in ILC composition and gene expression between tissues.

Distinct tissue-dependent composition and gene expression of human fetal innate lymphoid cells