The inositol phosphtase INPP4B sustains ILC1s and intratumoral NK cells through an AKT-driven survival pathway
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ABSTRACT:
PROVIDER: PRJNA1053379 | ENA |
REPOSITORIES: ENA
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Project description:Innate lymphoid cells (ILCs) are a heterogeneous population of lymphocytes that coordinate early immune responses and maintain tissue homeostasis. Type 1 immune responses are mediated by natural killer (NK) cells and group 1 ILCs (ILC1s). Despite their shared features, NK cells and ILC1s display profound differences among various tissue microenvironments. Here, we identify the inositol polyphosphatase INPP4B as a hallmark feature of tissue-resident ILC1s and intratumoral NK cells using a scRNA-seq atlas of tissue-associated and circulating NK/ILC1s. Conditional deletion of Inpp4b in ILC1s and NK cells reveals that it is necessary for the homeostasis of tissue-resident ILC1s but not circulating NK cells at steady-state. Inpp4b-deficient cells display increased rates of apoptosis and reduced activation of the pro-survival molecule AKT. Furthermore, expression of Inpp4b by NK/ILC1s is necessary for their presence in the intratumoral environment and lack of Inpp4b impairs antitumor immunity. These findings highlight INPP4B as a novel regulator of tissue residency and antitumor function in ILC1s and NK cells.
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Project description:Innate lymphoid cells (ILCs) are a heterogeneous population of lymphocytes that coordinate early immune responses and maintain tissue homeostasis. Type 1 innate immune responses are mediated by natural killer (NK) cells and group 1 ILCs (ILC1s). Despite their shared features, NK cells and ILC1s display profound differences among various tissue microenvironments. Here, we identify the inositol polyphosphatase INPP4B as a hallmark feature of tissue-resident ILC1s and intratumoral NK cells using an scRNA-seq atlas of tissue-associated and circulating NK/ILC1s. Conditional deletion of Inpp4b in ILC1s and NK cells reveals that it is necessary for the homeostasis of tissue-resident ILC1s but not circulating NK cells at steady-state. Inpp4b-deficient cells display increased rates of apoptosis and reduced activation of the prosurvival molecule AKT. Furthermore, expression of Inpp4b by NK/ILC1s is necessary for their presence in the intratumoral environment, and lack of Inpp4b impairs antitumor immunity. These findings highlight INPP4B as a novel regulator of tissue residency and antitumor function in ILC1s and NK cells.
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Project description:Group 1 innate lymphoid cells (ILCs) comprising circulating natural killer (cNK) cells and tissue-resident ILC1s are critical for host defense against pathogens and tumors. Despite a growing understanding of their role in homeostasis and disease, the ontogeny of group 1 ILCs remains largely unknown. Here, we used fate mapping and single-cell transcriptomics to comprehensively investigate the origin and turnover of group 1 ILCs. While cNK cells are continuously replaced throughout life, we uncovered tissue-dependent development and turnover of ILC1s. A first wave of ILC1s emerges during embryogenesis in the liver and transiently colonizes fetal tissues. After birth, a second wave quickly replaces ILC1s in most tissues apart from the liver, where they layer with embryonic ILC1s and persist until adulthood undergoing a unique developmental program. While embryonically-derived ILC1s give rise to a cytotoxic subset, the neonatal wave establishes a helper-like subset. Our findings uncover key ontogenic features of group 1 ILCs and their association with unique cellular identities and functions.
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2010-06-23 | E-GEOD-18005 | biostudies-arrayexpress
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Project description:Innate lymphoid cells (ILCs) comprise several subsets that were originally classified based on their cytokine production profiles. Natural killer (NK) cells and type 1 ILCs (ILC1s) were initially classified together, but recent data supported their separation into different lineages. Here we describe how infection with the parasite Toxoplasma gondii induces changes to NK1.1+ NKp46+ cells that persist independent of ongoing infection. Notably, there is an expansion of Eomes– CD49a+ cells that superficially resemble ILC1s, but express unique genes, circulate throughout the vasculature, and possess distinct epigenetic marks. Single-cell RNA sequencing confirms T. gondii-induced Eomes– CD49a+ cells are distinct from both conventional NK cells and ILC1s. Furthermore, there is heterogeneity within this population, as both conventional NK cells and ILC1s contribute to their formation. Indeed, downregulation of Eomes within conventional NK cells accounts for most T. gondii-induced Eomes– CD49a+ cells, indicating that NK cells can give rise to cells resembling ILC1s during infection.
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Project description:Innate lymphocytes are integral components of the cellular immune system that coordinates host defense against a multitude of challenges and can trigger immunopathology when dysregulated. Natural killer (NK) cells and innate lymphoid cells (ILCs) are innate immune effectors postulated to functionally mirror conventional cytotoxic T lymphocytes and helper T cells, respectively. Here, we show that the cytolytic molecule granzyme C was surprisingly expressed in cells with the phenotype of type 1 ILCs (ILC1s) in mouse liver and salivary gland. Cell fate-mapping and transfer studies revealed that granzyme C-expressing innate lymphocytes could be derived from ILC progenitors and did not interconvert with NK cells, ILC2s, or ILC3s. Granzyme C defined a maturation state of ILC1s, which required the transcription factor T-bet and to a lesser extent Eomes specifically in the salivary gland for their maintenance. Furthermore, transforming growth factor-b (TGF-b) signaling promoted maintenance of granzyme C-expressing ILC1s in the salivary gland and in the tumor of a transgenic breast cancer model, and their depletion caused accelerated tumor growth. ILC1s gained granzyme C expression following interleukin-15 (IL-15) stimulation, which enabled perforin-mediated cytotoxicity. Strikingly, constitutive activation of the IL-15-regulated transcription factor Stat5 in granzyme C-fate-mapped ILC1s triggered lethal perforin-dependent autoimmunity in neonatal mice. Thus, granzyme C marks a cytotoxic effector state of ILC1s, broadening their function beyond ‘helper-like’ lymphocytes.
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Project description:Signal transduction processes mediated by phosphatidyl inositol phosphates affect a broad range of cellular processes such as cell cycle progression, migration and cell survival. The protein kinase AKT is one of the major effectors in this signaling network. Chronic AKT activation contributes to oncogenic transformation and tumor development. Therefore, new small drugs were designed to block AKT activity for cancer treatment. Here we characterize the biological effects of the phosphatidyl inositol phosphate analogs SH-5 and SH-6 in colorectal cancer cell lines. We demonstrate that the two compounds did not reduce AKT phosphorylation significantly in the presence of growth factors, but induce a broad range of morphological and transcriptional alterations. Transcriptomic profiling in inhibitor-treated SW480 cells revealed a cluster of down- regulated genes associated with mitosis. Moreover, the treatment of SW480 cells with either SH-5 or SH-6 caused the formation of binucleated cells as a result of a specific abscission defect.
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