Arming the neighborhood watch Transcriptional networks underlying effector differentiation of ILC1s and other tissue resident lymphocytes

Innate lymphoid cells (ILCs) are a group of lymphocytes involved in rapid protection against invading pathogens. Although their existence has long evaded scientists, research into ILC differentiation and function has been accelerated after their recent discovery because of the presence of striking functional parallels with T cells. Many aspects of ILC1 biology, including the transcriptional programs that control ILC1 differentiation and function after they assume residency in tissues have remained incompletely understood. In this thesis, we have taken advantage of our recently developed Hobit reporter/deleter mice to specifically study how ILC1s are maintained in tissues and how they develop into cells with immediate effector potential. We analysed lineage-committed ILC1s using single-cell RNA sequencing and revealed substantial heterogeneity in the liver ILC1 population. We identified TCF-1⁺ CD127⁺ ILC1s that exhibited a classical helper-like profile and TCF-1^- CD127^- ILC1s with a cytotoxic-like profile. The helper-like and cytotoxic-like ILC1 subsets represented early and late maturation stages of ILC1s that were connected along a developmental path. We argue that ILC1 differentiation occurs in a multistep process regulated by distinct sets of TFs that sequentially control development, lineage specification and effector maturation. Importantly, our findings suggest that lineage committed ILC1s that emerge in tissues retain potential to acquire effector differentiation steps through a TF regulated pathway. We show that this transcriptional pathway of terminal differentiation is similarly active in other resident lymphocytes including iNKT and T_RM cells, thereby highlighting intriguing parallels in their transcriptional regulation.