Utveckling av medfödda fetala lymfoida celler i människa

Innate lymphoid cells (ILC), including NK cells, ILC1, ILC2, and ILC3, are involved in regulation of lymphoid tissue-development, and play important roles in viral and bacterial infections, cancer, inflammation and tissue-repair.

Although we now know that human ILCs are present early during human fetal development, the developmental pathways, lineage relationships and tissue-specific biology of fetal ILCs remains largely unknown.

Here we will test the hypothesis that there are tissue-specific molecular imprints on fetal ILCs that are maintained into adulthood, and that distinct ILC subsets can develop from tissue-restricted CD34+ hematopoietic progenitor cells (HPCs).

We will combine 19-color cell sorting with single cell RNA sequencing to perform in vivolineage tracing of human ILC development from HPCs to mature cells by analysis of somatic mutations in mitochondrial genes, allowing us to map the phylogeny of human fetal ILCs from CD34+ HPCs to mature stages at the single cell level across tissues.

Our approach also allows us to simultaneously determine tissue-specific imprints on fetal ILCs, and whether such imprints are maintained in adult tissues.

We believe that the proposed project is not only important for a better basic understanding of human fetal hematopoiesis, but also has implications for tissue-specific immunity, in utero adoptive-transfer therapies, fetal-maternal immunotolerance, and hematopoietic stem cell-based therapies.