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Innate lymphoid cells (ILC), including NK cells, ILC1, ILC2, and ILC3, are involved in lymphoid tissue-development, infections, cancer, inflammation and tissue-repair. We have recently shown that ILCs develop early, with distinct distribution and gene expression depending on tissue. In this application we will investigate the development and diversity of human fetal ILCs and their progenitors at clonal level. We hypothesize that development from tissue-restricted ILC progenitors together with clonally heritable gene expression and the tissue environment shape the development and diversity of human ILCs across tissues. By analyzing somatic mutations in mitochondrial genes, coupled with gene and protein expression at single cell level we aim at performing lineage tracing based on mutational patterns in human fetal ILC across tissues. To verify the results from the in vivo fate mapping data and to gain further insight into ILC development, we will dissect the potential of individual CD34+ HPCs to differentiate to mature ILCs in vitro. Finally, we aim at determining clonally heritable gene expression (clonal memory) in ILCs, enabling us to assess to what extent clonal memory contributes to tissue-dependent differences, as well as to dissect gene expression regulation in ILCs. We believe that the proposed project is important for a better basic understanding of human fetal hematopoiesis, as well as for tissue-specific immunity and hematopoietic stem cell-based therapies.