Defining factors that control human innate lymphoid cell development and function

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Innate lymphoid cells (ILCs) are a family of lymphocytes with pivotal roles in orchestrating immune responses and regulating tissue homeostasis. While inflammatory ILCs serve important functions in host defence and anti-tumour immunity, we and others have identified regulatory ILC populations that inhibit immune responses or recruit other suppressive cells. Animal studies have provided a roadmap of transcriptional networks that control ILC identity and function, yet studies of human ILCs are relatively scarce. Studies addressing human ILCs development, regulation and plasticity are greatly needed to understand pathways that direct human ILC development and determine how microenvironment factors influence their function. This research is centred on delineating molecular mechanisms that control human ILC development and function, with a particular focus on regulatory ILCs. Aim 1: Define key pathways that drive ILCreg development and function. We aim to identify pathways and transcription factors involved in regulatory ILC development and function using advanced genomics platforms. Induced regulatory ILCs will be contrasted with canonical ILCs using established methods to isolate and expand in vivo-derived human ILCs. Relevance of pathways and molecules associated with immunosuppressive functions and tissue repair activity will then be explored. Aim 2: Examine the plasticity of induced regulatory ILCs and canonical human ILC subsets. How different cytokines and microenvironment factors influence circulating and tissue-resident human ILCs from healthy individuals has not been determined. We aim to determine the stability or plasticity of human ILCs in blood and healthy human tissues (kidney, pancreas, spleen) by isolating ILCs, exposing them to various cytokines and profiling them at the epigenetic, transcriptional and protein level using advanced genomic and immunological platforms. Induced regulatory ILCs will also be examined for their ability to maintain their phenotype or convert to other ILC subsets with cytokine stimulations.  Aim 3: Assess the role of transcription factors in ILC development and function. A key question is whether there is a lineage defining transcription factor for regulatory ILCs. RNAseq analysis of human in vivo-derived regulatory ILCs identified transcription factors of interest, and Aim 1 aims to identify transcription factors that distinguish induced regulatory ILCs. Here, we will explore the role of several transcription factors in human ILC development and function using a lentiviral gene transfer system. Gene expression networks and ILC functions downstream of these transcription factors will be examined, the influence of regulatory ILC-associated transcription factors on ILC development and function determined. Novelty: Our studies of ILCregs and human ILCs from healthy individuals will expand our understanding of molecular pathways that control human ILC development and function.