Similar Datasets
Project description:Effective responses to intracellular pathogens are characterized by T cell clones with a broad affinity range for their cognate peptide and diverse functional phenotypes. How T cell clones are selected throughout the response to retain a breadth of avidities remains unclear. Here, we demonstrate that direct sensing of the cytokine IFN-γ by CD8+ T cells coordinates avidity and differentiation during infection. IFN-γ promotes the expansion of low-avidity T cells, allowing them to overcome the selective advantage of high-avidity T cells, whilst reinforcing high-avidity T cell entry into the memory pool, thus reducing the average avidity of the primary response and increasing that of the memory response. IFN-γ in this context is mainly provided by virtual memory T cells, an antigen-inexperienced subset with memory features. Overall, we propose that IFN-γ and virtual memory T cells fulfil a critical immunoregulatory role by enabling the coordination of T cell avidity and fate.
| S-EPMC10593754 | biostudies-literature
Project description:Interferon-γ couples CD8+ T cell avidity and differentiation during infection
| PRJNA1021655 | ENA
Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with
advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8
T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.
2023-06-16 | MSV000092193 | MassIVE
Project description:In this study we combined previous transcriptomics and immunopeptidomics data with new proteomics data from untreated and IFNg-treated CRC PDOs to dissect mechanisms that lead to remodeling of the immunopeptidome through IFNg treatment (this is from the paper introduction, let me know if it needs any stylistic changes). · Experiment description: The cells were grown in DMEM/F12 media with 20% fetal bovine serum, 1X Glutamax, 100 units/ml penicillin/streptomycin and 2% matrigel, and treated with 600ng/mL IFNg for 48 hours before harvesting. Cells were washed twice with ice-cold PBS then snap-frozen.
2023-09-29 | PXD031634 | Pride
Project description:Immune checkpoint blockade (ICB) leads to durable and complete tumour regression in some patients but in others gives temporary, partial or no response. Accordingly, significant efforts are underway to identify tumour-intrinsic mechanisms underlying ICB resistance. Results from a published CRISPR screen in a mouse model suggested that targeting STUB1, an E3 ligase involved in protein homeostasis, may overcome ICB resistance but the molecular basis of this effect remains unclear. Herein, we report an under-appreciated role of STUB1 to dampen the interferon gamma (IFNg) response. Genetic deletion of STUB1 increased IFNGR1 abundance on the cell surface and thus enhanced the downstream IFNg response as showed by multiple approaches including Western blotting, flow cytometry, qPCR, phospho-STAT1 assay, immunopeptidomics, proteomics, and gene expression profiling. Human prostate and breast cancer cells with STUB1 deletion were also susceptible to cytokine-induced growth inhibition. Furthermore, blockade of STUB1 protein function recapitulated the STUB1-null phenotypes. Despite these encouraging in vitro data and positive implications from clinical datasets, we did not observe in vivo benefits of inactivating Stub1 in mouse syngeneic tumour models - with or without combination with anti-PD-1 therapy. However, our findings elucidate STUB1 as a barrier to IFNg sensing, prompting further investigations to assess if broader inactivation of human STUB1 in both tumors and immune cells could overcome ICB resistance.
2022-08-18 | PXD035392 | Pride
Project description:CD8 T cell memory differentiation endows T cells with an ability to rapidly induce effector functions upon pathogen re-encounter. While it is well established that substantial epigenetic remodeling occurs during the effector stage of the immune response, the signaling events that imprint CD8 T cells with these stable epigenetic programs are not well-defined. To gain insight into the signaling determinants of effector-associated epigenetic programming among CD8 T cells, we explored the role of IL-12 in the imprinting of IFNg expression during human CD8 T cell priming. We observe that anti-CD3/CD28-mediated stimulation of human naïve CD8 T cells is not sufficient to induce substantial demethylation of the IFNg promotor. However, anti-CD3/CD28 stimulation in the presence of the inflammatory cytokine, IL-12, resulted in significant and stable demethylation of the IFNg locus that was commensurate with an increase in IFNg expression. We further show that IL-12-associated demethylation of the IFNg locus is coupled to cell division through TET2-dependent demethylation in an ex vivo human CAR T cell model system and an in vivo immunologically competent murine system. Collectively, these data illustrate that IL-12 signaling promotes TET2-mediated effector epigenetic programming in CD8 T cells during the primary immune response and serve as proof of concept that signal 3 cytokines can be used to guide the induction of epigenetically regulated traits among T cells used for adoptive immunotherapies.
2021-08-31 | GSE182968 | GEO
Project description:Cytotoxic CD8+ T cells can effectively kill target cells by producing cytokines, chemokines and granzymes. Expression of these effector molecules is however highly divergent, and tools that identify and pre-select potent killer cells are lacking. Human CD8+ T cells can be divided into IFNGand IL-2 producing cells. Unbiased RNA-sequencing and proteomics analysis on cytokine-producing fixed CD8+ T cells revealed that IL-2+ T cells produce helper cytokines, and that IFNG+ T cells produce cytotoxic molecules. IFNG+ cytotoxic T cells expressed the surface marker CD29 already prior to stimulation. CD29 also marked T cells with cytotoxic gene expression from different tissues in single-cell RNA-sequencing data. Notably, the cytotoxic features of CD29+ T cells were maintained during cell culture, suggesting a stable phenotype. Pre-selecting CD29-expressing MART1 TCR-engineered T cells potentiated the killing of target cells. We therefore propose that selecting for CD29+ T cells could boost the anti-tumoral activity of T cell therapeutics.
2021-09-08 | PXD012874 | Pride
Project description:Timecourse analysis of Interferon-Gamma (IFNg) signalling in mice deficient for IFNg or both IFNg and Suppressor of Cytokine Signalling-1 (SOCS1). Keywords: time course expression analysis
2006-02-14 | GSE4232 | GEO
Project description:Gene expression profiling of C57Bl/6 wild type and IFNg-deficient whole ileum at 8 weeks of age 5 wild type control, 5 IFNg knockout
2016-07-16 | E-GEOD-69635 | biostudies-arrayexpress
Project description:The pandemic rise of Zika virus (ZIKV) has recently commanded the attention of the general public and medical research community alike . The characterization of exact molecular components of immune response associated may help design more effective therapeutic interventions. In this study, we aimed to characterize the immune signature of ZK-specific CD8 T cells after stimulation with ZK specific peptides comparing it with a generic stimulation with anti-CD3/CD28. Transcriptomic profiling using RNA sequencing was performed on CD8 T cells producing IFNg in comparison with non IFNg producing cells isolated from individuals with Zika infections from endemic areas of Puerto Rico and US travellers.
2019-01-23 | GSE105884 | GEO