IL-1R8 is a checkpoint in NK cells regulating anti-tumor and anti-viral activity
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE105043 | GEO | 2017/11/02
SECONDARY ACCESSION(S): PRJNA416792
REPOSITORIES: GEO
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Project description:Natural killer (NK) cells can be divided into phenotypic subsets based on the expression of receptors that bind self-MHC-I molecules with differing affinities; a concept termed licensing or education. Here we show that NK cell subsets exhibit markedly different migratory, effector, and immunoregulatory functions on dendritic cells and antigen-specific CD8+ T cell responses during influenza and murine cytomegalovirus infections. Shortly after infection, unlicensed NK cells preferentially trafficked to draining lymph nodes and produced GM-CSF, which promoted the expansion and activation of dendritic cells, and ultimately resulted in sustained antigen-specific CD8+ T cell responses. In contrast, licensed NK cells preferentially migrated to infected parenchymal tissues and produced greater levels of interferon-γ (IFN-γ). Importantly, human NK cell subsets exhibited similar phenotypic characteristics and patterns of cytokine production. Collectively, our studies demonstrate a critical demarcation between the functions of licensed and unlicensed NK cell subsets, with the former functioning as the classical effector subset in inflamed tissues and the latter as modulators of adaptive immunity helping to prime immune responses in draining lymph nodes.
2017-08-22 | GSE72632 | GEO
Project description:Constitutively found at high frequencies, the role for NK cell proliferation remains unclear. Here, a shift in NK cell function from predominantly producing interferon-? (IFN-?), a cytokine with proinflammatory and antimicrobial functions, to producing the immunoregulatory cytokine IL-10, is defined during extended murine cytomegalovirus infection. The NK cells driven to express IL-10 in vivo acquired responsiveness to IL-12 and IL-21 for IL-10 production, but neither cytokine was required for the endogenous response. In vitro studies with IL-2 to support proliferation and in vivo adoptive transfers into murine cytomegalovirus-infected mice demonstrated that NK cell proliferation and further division enhanced the change. During infection, the responding NK cells acquired histone modifications indicative of an open IL-10 gene, and an IL-10 response was proliferation dependent ex vivo if the NK cells had not yet expanded in vivo but independent if they had. Thus, a novel role for proliferation in supporting changing innate cell function is discovered. The chromatin status of ex vivo isolated NK cells during MCMV infection was investigated by ChIP-seq on histone epigenetic marks (H3K4m3, H3K27m3, H3K36m3) on day 0, day 1.5 and day 3.5 post infection.
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2022-01-12 | GSE176208 | GEO
Project description:The mechanisms underlying human NK cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins following cytomegalovirus (CMV) infection. The absence of B and myeloid cell-related signaling protein expression in these NK cell subsets correlated with promoter DNA hypermethylation. Intriguingly, geneome-wide analyses revealed patterns of DNA methylation that were strikingly similar between CMV-associated adaptive NK cells and cytotoxic effector CD8+ T cells, but differed from those of canonical NK cells. A total of 23 samples were analyzed (4 sorted NK cell subsets and 2 sorted T cell subsets each from 4 individual donors). In one donor only 5 subsets were analyzed. Bisulfite-converted genomic DNA was hybridized to the Illumina Human Methylation450 BeadChip
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Project description:Natural killer (NK) cells are an innate immune cell type that serves at the first level of defense against pathogens and cancer. NK cells have clinical potential; However, multiple current limitations exist that naturally hinder the successful implementation of NK cell therapy against cancer, including their effector function, persistence, and tumor infiltration. To unbiasedly identify genes underlying critical NK cell characteristics against cancer, we perform functional mapping of tumor infiltrating NK (TINK) cells by both in vivo AAV-CRISPR screens and single-cell sequencing. We establish a strategy with AAV-SleepingBeauty(SB)-CRISPR screening leveraging a focused high-density sgRNA library, and perform four independent in vivo tumor infiltration screens of primary NK cells in mouse models of melanoma, breast cancer, pancreatic cancer, and glioblastoma. In parallel, we characterize single-cell transcriptomic landscapes of tumor-infiltrating NK cells, which identifies previously unexplored sub-populations of NK cells with distinct expression profiles, a shift from immature to mature NK (mNK) cells in the tumor microenvironment (TME), and decreased expression of mature marker genes in mNK cells. CALHM2, a calcium homeostasis modulator previously not linked to NK function, emerges as a convergent hit from both CRISPR screen and single-cell data. CALHM2 knockout NK cells show enhancement of in vitro cytotoxicity and in vivo tumor infiltration in both mouse primary NK and human chimeric antigen receptor (CAR)-NK cells. Re-introduction of CALHM2 mRNA reverses CALHM2 knockout phenotype of NK cytotoxicity and degranulation. Importantly, in a solid tumor model that is completely resistant to adoptive cell therapy of unmodified CAR-NK cells, CALHM2 knockout CAR-NK cells show potent in vivo anti-tumor efficacy. Human primary NK cell study with multiple donors reveals that CALHM2 knockout enhances cytotoxicity, degranulation and cytokine production of NK cells. Transcriptomics profiling of human primary NK cells reveal multiple enriched pathways of downstream genes upon CALHM2 knockout in both baseline and stimulated conditions. These data identify endogenous cellular genetic checkpoints that naturally limit NK cell function, and pinpoint CALHM2 as a key factor in which genetic modification can be engineered to enhance NK cell-based immunotherapies.
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Project description:Natural killer (NK) cells are an innate immune cell type that serves at the first level of defense against pathogens and cancer. NK cells have clinical potential; However, multiple current limitations exist that naturally hinder the successful implementation of NK cell therapy against cancer, including their effector function, persistence, and tumor infiltration. To unbiasedly identify genes underlying critical NK cell characteristics against cancer, we perform functional mapping of tumor infiltrating NK (TINK) cells by both in vivo AAV-CRISPR screens and single-cell sequencing. We establish a strategy with AAV-SleepingBeauty(SB)-CRISPR screening leveraging a focused high-density sgRNA library, and perform four independent in vivo tumor infiltration screens of primary NK cells in mouse models of melanoma, breast cancer, pancreatic cancer, and glioblastoma. In parallel, we characterize single-cell transcriptomic landscapes of tumor-infiltrating NK cells, which identifies previously unexplored sub-populations of NK cells with distinct expression profiles, a shift from immature to mature NK (mNK) cells in the tumor microenvironment (TME), and decreased expression of mature marker genes in mNK cells. CALHM2, a calcium homeostasis modulator previously not linked to NK function, emerges as a convergent hit from both CRISPR screen and single-cell data. CALHM2 knockout NK cells show enhancement of in vitro cytotoxicity and in vivo tumor infiltration in both mouse primary NK and human chimeric antigen receptor (CAR)-NK cells. Re-introduction of CALHM2 mRNA reverses CALHM2 knockout phenotype of NK cytotoxicity and degranulation. Importantly, in a solid tumor model that is completely resistant to adoptive cell therapy of unmodified CAR-NK cells, CALHM2 knockout CAR-NK cells show potent in vivo anti-tumor efficacy. Human primary NK cell study with multiple donors reveals that CALHM2 knockout enhances cytotoxicity, degranulation and cytokine production of NK cells. Transcriptomics profiling of human primary NK cells reveal multiple enriched pathways of downstream genes upon CALHM2 knockout in both baseline and stimulated conditions. These data identify endogenous cellular genetic checkpoints that naturally limit NK cell function, and pinpoint CALHM2 as a key factor in which genetic modification can be engineered to enhance NK cell-based immunotherapies.
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Project description:Natural killer (NK) cells are an innate immune cell type that serves at the first level of defense against pathogens and cancer. NK cells have clinical potential; However, multiple current limitations exist that naturally hinder the successful implementation of NK cell therapy against cancer, including their effector function, persistence, and tumor infiltration. To unbiasedly identify genes underlying critical NK cell characteristics against cancer, we perform functional mapping of tumor infiltrating NK (TINK) cells by both in vivo AAV-CRISPR screens and single-cell sequencing. We establish a strategy with AAV-SleepingBeauty(SB)-CRISPR screening leveraging a focused high-density sgRNA library, and perform four independent in vivo tumor infiltration screens of primary NK cells in mouse models of melanoma, breast cancer, pancreatic cancer, and glioblastoma. In parallel, we characterize single-cell transcriptomic landscapes of tumor-infiltrating NK cells, which identifies previously unexplored sub-populations of NK cells with distinct expression profiles, a shift from immature to mature NK (mNK) cells in the tumor microenvironment (TME), and decreased expression of mature marker genes in mNK cells. CALHM2, a calcium homeostasis modulator previously not linked to NK function, emerges as a convergent hit from both CRISPR screen and single-cell data. CALHM2 knockout NK cells show enhancement of in vitro cytotoxicity and in vivo tumor infiltration in both mouse primary NK and human chimeric antigen receptor (CAR)-NK cells. Re-introduction of CALHM2 mRNA reverses CALHM2 knockout phenotype of NK cytotoxicity and degranulation. Importantly, in a solid tumor model that is completely resistant to adoptive cell therapy of unmodified CAR-NK cells, CALHM2 knockout CAR-NK cells show potent in vivo anti-tumor efficacy. Human primary NK cell study with multiple donors reveals that CALHM2 knockout enhances cytotoxicity, degranulation and cytokine production of NK cells. Transcriptomics profiling of human primary NK cells reveal multiple enriched pathways of downstream genes upon CALHM2 knockout in both baseline and stimulated conditions. These data identify endogenous cellular genetic checkpoints that naturally limit NK cell function, and pinpoint CALHM2 as a key factor in which genetic modification can be engineered to enhance NK cell-based immunotherapies.
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Project description:IL-1R8 is a checkpoint in NK cells regulating anti-tumor and anti-viral activity
| PRJNA416792 | ENA