Tissue-resident lymphocytes represent promising effectors to treat pathologies in tissues. However, because these cells are largely located in tissues, they cannot easily be isolated in humans, and we lack the basic knowledge that would enable their generation in vitro for immunotherapeutic purposes. In this project, I propose to investigate in mice the basic mechanisms underlying the development and the transcriptional programming of tissue-residency features of a recently identified lineage of lymphocytes: the innate lymphoid cells (ILC). My postdoctoral work contributed to the identification and characterization of several developmental stages at which tissue-residency features are programmed in ILC. I now identified the developmental intermediates that initiate ILC development and tissue-residency programming. This breakthrough enables me to characterize the process of ILC development and tissue-residency programming in detail, and puts me in a unique position to decipher the mechanisms that underly these processes. This is what I propose to begin in this project, by investigating the function of two transcription factors that I find play key roles in respectively (i) initiating ILC development and tissue-residency programming, and (ii) enabling tissue-residency of ILC in specific tissues. The results will provide knowledge on the transcription factors that control ILC development and tissue residency programming. They enable subsequent work in which these factors could be manipulated to promote the generation of tissue-resident lymphocytes, or to modulate their functions. This basic research project will thus have broad implications for human health.