JAK inhibition differentially affects NK cell and ILC1 homeostasis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE135116 | GEO | 2019/12/11
REPOSITORIES: GEO
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Project description:Janus kinase (JAK) inhibitors are widely used in the treatment of multiple autoimmune and inflammatory diseases. Immunologic and transcriptomic profiling have revealed major alterations on natural killer (NK) cell homeostasis associated with JAK inhibitions, while information on other innate lymphoid cells (ILCs) is still lacking. Herein, we observed that, in mice, the homeostatic pool of liver ILC1 was less affected by JAK inhibitors compared to the pool of NK cells present in the liver, spleen and bone marrow. JAK inhibition had overlapping effects on the transcriptome of both subsets, mainly affecting genes regulating cell cycle and apoptosis. However, the differential impact of JAK inhibition was linked to the high levels of the antiapoptotic gene Bcl2 expressed by ILC1. Our findings provide mechanistic explanations for the effects of JAK inhibitors on NK cells and ILC1 which could be of major clinically relevance.
| S-EPMC6930870 | biostudies-literature
Project description:JAK inhibition differentially affects NK cell and ILC1 homeostasis
| PRJNA557465 | ENA
Project description:Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from NK cells is a gene signature indicative of TGFb-family cytokine imprinting. To assess the impact of TGFb family cytokines on ILC1 differentation, we examined SMAD4- a transcription factor that facilitates the signaling pathway common to all TGFb family cytokines-was specifically ablated in ILCs and NK cells. While SMAD4 deficiency did not affect ILC1 differentation, NK cells paradoxically aquired an ILC1-like gene signature and were incapable of controlling tumor metastasis and viral infection. We used microarray to define the transcriptional differences between splenic NK cells from WT and SMAD4F/F x Ncr1-Cre mice.
2017-07-31 | GSE100247 | GEO
Project description:The development of innate lymphoid cell (ILC) transcription factor reporter mice has shown a previously unexpected complexity in ILC haematopoiesis. Using novel polychromic mice to achieve higher phenotypic resolution we have characterised bone marrow progenitors that are committed to the group 1 ILC lineage. These common ILC1/NK progenitors, which we call ‘aceNKPs’, are defined as lineage–Id2+IL-7Ra+CD25–a4b7–NKG2A/C/E+Bcl11b–. In vitro, aceNKPs differentiate into group 1 ILCs, including NK-like cells that express Eomes without the requirement for IL-15, and produce IFN-g and perforin upon IL-15 stimulation. Following reconstitution of Rag2–/–Il2rg–/– hosts, aceNKPs give rise to a spectrum of mature ILC1/NK cells (regardless of their tissue location) that cannot be clearly segregated into the traditional ILC1 and NK subsets, suggesting that group 1 ILCs constitute a dynamic continuum of ILCs that can develop from a common progenitor. In addition, aceNKP-derived ILC1/NK cells effectively ameliorate tumour burden in a model of lung metastasis where they acquired a cytotoxic NK cell phenotype. Our results identify the primary ILC1/NK progenitor that lacks ILC2 or ILC3 potential and is strictly committed to ILC1/NK cell production irrespective of tissue homing.
2022-11-02 | GSE213814 | GEO
Project description:Innate lymphoid cell (ILC) subsets that mirror helper T cells in their effector cytokine profiles have recently emerged as central players in both homeostatic and inflammatory conditions. Like their Th1, Th2 and Th17/Th22 helper T cell counterparts, ILC subsets are categorized based on their expression of specific transcription factors and effector cytokines: group 1 ILC (ILC1) express T-bet and IFN-γ; group 2 ILC (ILC2) express GATA-3 and type 2 effector cytokines such as IL-13 and IL-5; and group 3 ILC (ILC3) express RORgt and the cytokines IL-22 and/or IL-17. Under this nomenclature, natural killer (NK) cells and lymphoid tissue inducers (LTi) are considered ILC1 and ILC3, respectively. ILC1 contain both CD4+ and CD4- populations, but whether this phenotypic characteristic reflects functional differences between these two populations is unknown. These studies examine the gene expression profiles of CD4+ vs CD4- ILC1 in a cohort of healthy control subjects. ILC subsets were isolated from the peripheral blood of healthy control subjects. cDNA was isolated and amplified from sorted populations, and gene expression was analyzed by RNAseq
2015-12-31 | E-GEOD-69596 | biostudies-arrayexpress
Project description:We previously reported that JAK/STAT pathway-mediated regulation of IRF-related genes may have an important role in the disease activity of SLE through analyzing the difference of gene expression in peripheral blood CD3+ T cells obtained from SLE patients. Recently pan-JAK inhibitor (JAKi) tofacitinib (TOFA) were developed and successfully applied to patients with rheumatoid arthritis. Therefore, the application possibility of TOFA was investigated for the new therapeutic strategy of SLE. Anti-dsDNA antibody and proteinuria were decreased and glomerulo/interstitial nephritis were ameliorated in any TOFA administered SLE mice. In splenic CD4+ T cell analysis, naïve cells significantly increased and effector/memory cells decreased. TOFA with dexamethasone (DEXA) therapy showed tendency to indicate stronger inhibitory effect comparing with TOFA or DEXA monotherapy. The gene expression of Ifit3/IFIT3 that related with anti-viral IFN signaling pathway was significantly suppressed in both CD4+ from SLE mice and CD3+ T cells from SLE patients after treatment. Both TOFA monotherapy and dual therapy with DEXA could suppress nephritis and modify immunological function in SLE mice with different genetic background. IFN signaling pathway was supposed to be important for the functional mechanism of TOFA to improve the disease condition. TOFA may contribute to the development of a new therapeutic strategy for SLE. The gene expression analysis was compared among tofacitinib, tofacitinib+dexamethsone, dexamethsone and non-treated control groups and extracted TOFA specific decreased genes in NZBWF1 mice.
2016-03-03 | E-GEOD-78825 | biostudies-arrayexpress
Project description:Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) require the transcription factor STAT4 to elicit rapid effector responses and protect against pathogens. Herein, by combining genetic and transcriptomic approaches, we revealed that STAT4 played an unexpected divergent role in regulating effector differentiation of murine ILC1 and NK cells, during intestinal inflammation. Stat4 deletion in Ncr1-expressing cells led to an increased generation of cytotoxic ILC1 in the inflamed large intestine. By contrast, Stat4-deficient NK cells showed impaired terminal differentiation, characterized by lower levels of IRF-8 and KLRG1. STAT4 expression in NCR+ innate lymphocytes restrained gut inflammation and controlled both systemic IFN-g levels and the number of type 2 adaptive T cells in the large intestine. Collectively our data shed light on shared and distinctive mechanisms of transcriptional regulation driven by STAT4 in NK cells and ILC1 required for protection during intestinal inflammation.
2023-09-28 | GSE210977 | GEO
Project description:Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) require the transcription factor STAT4 to elicit rapid effector responses and protect against pathogens. Herein, by combining genetic and transcriptomic approaches, we revealed that STAT4 played an unexpected divergent role in regulating effector differentiation of murine ILC1 and NK cells, during intestinal inflammation. Stat4 deletion in Ncr1-expressing cells led to an increased generation of cytotoxic ILC1 in the inflamed large intestine. By contrast, Stat4-deficient NK cells showed impaired terminal differentiation, characterized by lower levels of IRF-8 and KLRG1. STAT4 expression in NCR+ innate lymphocytes restrained gut inflammation and controlled both systemic IFN-g levels and the number of type 2 adaptive T cells in the large intestine. Collectively our data shed light on shared and distinctive mechanisms of transcriptional regulation driven by STAT4 in NK cells and ILC1 required for protection during intestinal inflammation.
2023-09-28 | GSE210483 | GEO
Project description:Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from NK cells is a gene signature indicative of TGFb-family cytokine imprinting. To assess the impact of TGFb family cytokines on ILC1 differentation, we examined SMAD4- a transcription factor that facilitates the signaling pathway common to all TGFb family cytokines-was specifically ablated in ILCs and NK cells. While SMAD4 deficiency did not affect ILC1 differentation, NK cells paradoxically aquired an ILC1-like gene signature and were incapable of controlling tumor metastasis and viral infection. We used microarray to compare the transcriptional differences between human blood NK cells. NK cells from a patient with a deleterious SMAD4 mutation or control NK cells were cultured overnight with either IL-2 alone or TGFb1 and IL-2.
2017-07-31 | GSE100246 | GEO
Project description:Mice were weaned onto standard RM1 diet or onto a highly palatable obesogenic diet (824018 – ‘45% AFE fat) supplemented with condensed milk. After 12 weeks, mice were killed, and liver NK cells (Lin- NK1.1+ CD49a- CD49b+) or ILC1 (Lin- NK1.1+ CD49a+ CD49b-) were sorted. Total RNA was extracted from sorted cells, cDNA generated and RNASeq performed.
2019-03-13 | GSE122828 | GEO