Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA116943 | ENA |
REPOSITORIES: ENA
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Project description:Recently, tumor-associated neutrophils (TANs) are considered as an important component of the tumor microenvironment. Here, we show that a specific genetic deficiency of neutrophils induced accelerated mesenchymal carcinogenesis associated with a deficient production of IFN-γ in the tumor microenvironment. Unexpectedly, increased susceptibility to cancer of neutropenic mice was associated with impaired type 1 polarization of unconventional T cell (UTC) subsets, namely mucosal-associated invariant T (MAIT) cells and double CD4 and CD8 negative TCRβ+ T (DNT) cells, resulting in reduced expression of T-bet and IFN-γ and increased expression of Rorγt and IL-17A. Here, we uncovered a new mechanism by which neutrophils induced an IL-12-dependent type 1 polarization of MAIT and DNT cells characterized by the upregulation of T-bet expression. Therefore, a systemic reconstitution of Csf3r-/- mice with functional naïve neutrophils was sufficient to restore UTCs activation state and to slow down sarcoma growth. Finally, in patients with undifferentiated pleomorphic sarcoma, TAN infiltration signature was associated with better overall survival and increased expression of IFN-γ and type 1 inflammatory response signature.
2019-06-24 | GSE109031 | GEO
Project description:CD8+ cytotoxic T lymphocytes (CTLs) play a major role in defense against intracellular pathogens, and their functions are specified by antigen recognition and innate cytokines. While effector CTLs eliminate the infection, a small population of memory cells are retained that yields more rapid and robust response upon re-infection. Antigen presenting cells secrete an array of innate cytokines including IL-12 and IFN-α after recognition of pathogens. Both IL-12 and IFN-α have been shown to act as the third signal regulating the development of CTLs. We have shown that these two cytokines have a non-redundant effect in generation of human effector CTL. IL-12 alone is sufficient for effector CTL genesis marked by IFN-γ and TNF-α production, as well as increased cytolytic activity. Even in the presence of IFN-α, IL-12 programs CTLs that express the chemokine receptor CXCR3 and effector cytokines. Using microarray analysis we have investigated how IL-12 and IFN-α differentially regulate the genetic programming pathways that give rise to effector CTLs among multiple human donors. We have also analyzed the gene expression patterns of cells sorted from healthy human peripheral blood that display surface markers of effector memory CTL (designated as ex vivo) samples. 5 healthy human donor samples were used for the in vitro cultures. For each donor the CFSE labeled cells (CD8+CD45RA+) were cultured in the presence of neutralized, IL-12, IFN-a, and IL-12+IFN-a conditions and plate-bound anti-CD3+anti-CD28 for 3.5 days. Total RNA from CFSEhi (Undiv) and CFSElo (Div) sorted cells were used for Illumina Bead Array. 4 healthy human donor samples were used for the ex vivo samples. Total RNA was collected from FACS sorted CD8+CCR7hiCXCR3lo and CD8+CCR7loCXCR3hi cells without any stimulation.
2011-09-29 | E-GEOD-27337 | biostudies-arrayexpress
Project description:Dr. Jameson's research focus is on development and regulation of lymphocytes, especially T cells. Recent work has suggested that differential glycosylation effects the sensitivity of the T cell receptors and its coreceptors, suggesting that regulation of glycosylation may be a critical element in controlling T cell development, survival and functional activity. Determination of how glycosylation enzymes/substrates change in gene expression during development of mouse CD8 T cells. Highly purified pre-selection CD4+8+ thymocytes (using transgenic/knockout mice in our colony) are compared to mature CD8 T cells from the lymph node. The goal is to build on data suggesting that this developmental step involves regulated expression of sialyltransferases (and/or neuraminidases). Highly purified pre-selection CD4+8+ thymocytes (using transgenic/knockout mice in our colony) are compared to mature CD8 T cells from the lymph node. Pre-selection CD4+8+ (DP) thymocytes were sorted from TCRa-/- thymi. Post-selection (post-positive selection) DP thymocytes came from an OT-I TCR transgenic mouse. Naïve (CD44lo) CD8 T cells from lymph node of OT-I mice were used as naïve CD8 T cells. For activated cells, naïve OT-I T cells were activated for 48 hours in vitro with cognate antigen (SIINFEKL peptide/Kb) (displayed on cell sized latex beads) in the presence of IL-2 and IL-12.
2010-12-11 | E-GEOD-26012 | biostudies-arrayexpress
Project description:Activated naïve (aNAV) B cells have been shown to be the precursor of the CD11c+T-bet+ IgD−CD27− double negative (DN)2 or atypical memory (aMEM) B cells in systemic lupus erythematosus (SLE). To determine factors that maintain resting naïve (rNAV) B cells, the transcriptomics program in naïve (IGHD+IGHM+) B cells in human healthy controls (HC) and SLE was analyzed by single cell RNA-sequencing analysis. In HC, naive B cells expressed IL-4 pathway genes whereas in SLE, naive B cells expressed type I interferon stimulated genes (ISGs). In HC, aNAV B cells exhibited upregulation of gene signature of germinal center (GC) and classical memory (cMEM) B cells. In contrast, in SLE, aNAV B cells expressed signature genes of aMEM. In vitro exposure of SLE B cells to IL-4 promoted B cell development into CD27+CD38+ plasmablasts/plasma and IgD−CD27+ cMEM B cells. The same treatment blocked the development of CD11c+Tbet+ aNAV and DN2 B cells and preserved DN B cells as CD11c−Tbet− DN1 B cells. Lower expression of IL-4R and increased intracellular IFN-β in naïve B cells was correlated with the accumulation of CD21−IgD− B cells and the development of anti-Smith and anti-DNA autoantibodies in SLE patients (n=47). Our results show that IL-4R and type I IFN signaling in naïve B cells induce the development of distinct lineages of cMEM versus aMEM B cells, respectively. Further, a diminished IL-4R signaling shifted activated B-cell development from the DN1 to the DN2 trajectory in SLE patients. Therapies that enhance IL-4R signaling may be beneficial for ISGhi SLE.
2022-08-12 | GSE136035 | GEO
Project description:CD8 T cells play a central role in antiviral immunity. Type I interferons are among the earliest responders after virus exposure and can cause extensive reprogramming and antigen-independent bystander activation of CD8 T cells. Although bystander activation of pre-existing memory CD8 T cells is known to play an important role in host defense and immunopathology, its impact on naïve CD8 T cells remains underappreciated. Here we report that exposure to reovirus, both in vitro or in vivo, promotes bystander activation of naïve CD8 T cells within 24 hours and that this distinct subtype of CD8 T cell displays an innate, antiviral, type I interferon sensitized signature. The induction of bystander naïve CD8 T cells is STAT1 dependent and regulated through nicotinamide phosphoribosyl transferase (NAMPT)-mediated enzymatic actions within NAD+ salvage metabolic biosynthesis. These findings identify a novel aspect of CD8 T cell activation following virus infection with implications for human health and physiology.
2023-01-30 | PXD039614 | Pride
Project description:Human primary monocytes are composed of a minor, more mature CD16+(CD14low/neg) population and a major CD16neg(CD14+) subset. The specific functions of CD16+ vs. CD16neg monocytes in steady state or inflammation remain poorly understood. In previous work we found that IL-12 is selectively produced by the CD16+ subset in response to the protozoan pathogen, Toxoplasma gondii. Here we demonstrated that this differential responsiveness correlates with the presence of an IFN-induced transcriptional signature in CD16+ monocytes already at baseline. Consistent with this observation, we found that in vitro IFN-γ-priming overcomes the defect in IL-12 response of the CD16neg subset. We have anayzed the gene expression profile of primary human CD16+ and CD16neg monocyte subsets cultured for without or with IFN-gamma
2021-01-07 | GSE164346 | GEO
Project description:Differentiation of naive CD8 T cells into cytotoxic effector cells requires three distinct signals- antigen (signal 1), costimulation -B7-1 (signal 2) and cytokine, either interleukin-12, interferon-a/b, or IL-21 (signal 3). Interaction of naive CD8 T cells with antigen and B7-1 programs cell division and proliferation whereas the presence of cytokines- IL-12, IFNa/b or IL-21 promote survival, differentiation and memory establishment. In the absence of signal 3, the cells interacting with antigen/B7-1 undergo tolerance induction. Previous work had analyzed the regulation of mRNA expression changes induced by IL-12 and IFN-a and cells stimulated with antigen, B7-1 and cytokine by comparing mRNA expression levels in naïve CD8 T cells, cells stimulated with 2 signals (antigen and B7-1) (Agarwal, P.A., A. Raghavan, S.L. Nandiwada, J.M. Curtsinger, P.R. Bohjanen, D.L. Mueller and M.F. Mescher. Gene regulation and chromatin remodeling by IL-12 and Type I interferon in programming for CD8 T cell effector function and memory. J. Immunol. 183:1695-1704 (2009). PMCID: PMC2893405). That microarray data was deposited in the NCI GEO database and can be found at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc_GSE15930. The objective of the current study was to carry out the same analysis to determine IL-21-dependent changes in mRNA expression in CD8 T cells responding to antigen and B7-1-dependent costimulation in the absence or presence of IL-21.
2015-09-30 | GSE70136 | GEO
Project description:In this model, TLR2-TLR6 mediates MyD88 pathway gets activated, which activates IL-12 production and induces iNOS expression when the Macrophage is infected with Leishmania parasite. The early induction of IL-10 takes place which leads to the induction of NFIL3, HDAC3, and SHP-1. They inhibit IL-12 production and thus hamper IL-12 induced IFN-gamma mediated; Nitric oxide production. A key transcription factor NFAT5 connects IL-12 and IL-10 pathways. It upregulates IL-12 and downregulates IL-10. In this model, NFAT5 is downregulated which is also inhibiting IL-12.
2022-01-24 | MODEL2012040002 | BioModels
Project description:To investigate the impact of paracrine IL-2 signals on memory precursor (MP) cell differentiation., we activated CD8 T cell in vitro in the presence or absence of exogenous IL-2 (ex-IL-2). We assessed the memory differentiation of activated T cells by transfer into virus-infected mice. Both conditions generated CD8 T cells that participate in the ongoing immune response and gave rise to similar memory cells. Conversely, when transferred into a naive host, T cells activated with ex-IL-2 generated a higher frequency of memory cells displaying increased functional memory traits. Single-cell RNA-seq analysis indicated that without ex-IL-2, cells rapidly acquire a MP signature, while in its presence they adopted an effector signature. This was confirmed at the protein level and in a killing assay. Overall, ex-IL-2 delays the transition into MP cells, allowing the acquisition of effector functions that become imprinted in their progeny. These findings may help to optimize the generation of therapeutic T cells.
2024-02-22 | GSE237866 | GEO
Project description:The crosstalk between intestinal epithelial cells (IEC) and Th17-polarized CD4+ T-cells is critical for mucosal homeostasis, with HIV-1 causing major alterations in people living with HIV (PLWH) despite antiretroviral therapy (ART). Here, we used a model of IEC:T-cell co-culture to investigate the effects of IL-17A and TNF, two cytokines produced by Th17-cells, in regulating IEC ability to promote de novo infection and viral outgrowth from reservoir cells. Our results demonstrated that IL-17A in the presence/absence of TNF acts on IEC to increase HIV capture and trans infection of CD3/CD28-activated T-cells from uninfected individuals. Also, IL-17A-exposed IEC significantly increased HIV replication and outgrowth in CD3/CD28-activated T-cells infected with HIV in vitro and isolated from ART-treated PLWH, respectively. Exposure of IEC to IL-17A resulted in decreased type I IFN levels, as measured using the 293T-KEK cell based assay. Illumina RNA sequencing performed on cytokine-activated IEC before/after co-culture with T-cells of ART-treated PLWH revealed a molecular signature associated with IL-17A-mediated proviral effects. This signature includes decreased expression of transcripts linked to type I IFN production/response (DDX60, IRF7, STAT1) and HIV restriction (IFITM1, TRIM5, IF2AK2, MX1, MX2, IFIT1,3,5, PARP12, HERC6, ISG15, viperin, BST2, OAS2/3), and increased expression of Th17-attracting chemokines (CCL20).
2021-03-01 | GSE147045 | GEO