Sunday, May 11, 2025
5/11/2025
Transcriptional Regulation of Innate-Like T Cells - Innate lymphocytes include ILCs and innate-like NKT/MAIT/gamma-delta T lymphocytes that characteristically acquire Th1-, Th2- or Th17-like helper programs as well as tissue-resident properties during development in the bone marrow or thymus. In that respect, they differ fundamentally from their adaptive T cell counterparts, which are born naïve and recirculating, and only acquire tissue resident effector properties after exposure to pathogens and cytokines. Our research focuses on understanding the different mechanisms that control the parallel development of these populations in very different contexts. While we previously reported that the transcription factor (TF) PLZF was a common signature of innate lineages that directed their innate developmental fate, this project focuses on the layer of regulatory enhancers that differentially control the helper lineage-specific TFs Gata-3, T-bet and RORgt in innate and in adaptive lymphocytes, with emphasis on NK cells. We develop an epigenetic approach that identifies these enhancers and we generate enhancer reporter strains that are used to specifically manipulate innate and adaptive populations. The advantage of this approach is that epigenetic markers appear earlier and are more stable than the TF that they regulate. They also provide more complexity and specificity to dissect these developmental programs. In support of this approach, we recently identified a dedicated, ILC2- specific enhancer and generated mice lacking this enhancer to dissect the respective contribution of innate and adaptive type 2 responses in models of allergic airway inflammation. Here, we will apply this new approach to elucidate the issues of identity and relationship between NK cells and other group I lymphocytes, which express closely related properties and a degree of plasticity that have greatly confounded prior studies. The specific aims will (SA#1) identify candidate enhancers of the NK developmental pathway through a genome-wide bioinformatic search; (SA#2) validate these enhancers in vivo through CRISPR deletions; (SA#3) generate enhancer-reporter strains that specifically identify and manipulate NK cells. These studies will provide novel insights into the complexity and specificity of Group 1 Innate Lymphocytes, and generate new tools to probe their respective contributions in homeostasis and in tumor, infection and autoimmune conditions. RELEVANCE (See instructions): Our studies investigate a recently uncovered population of so-called innate lymphocytes. These cells act early in the immune response and provide major contributions in maintaining tissue health and in regulating the response in tumors, infections, allergy and autoimmune conditions. Specifically, we develop new genetic mouse models that will help define the differences between NK cells and ILC1s, two related subtypes that exert potent but distinct contributions against tumors and viral infections in mouse and human.
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