TCR affinity defines tumor-specific CD8 T cell differentiation and dysfunction [RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE141817 | GEO | 2021/12/11
REPOSITORIES: GEO
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Project description:ATACseq analysis of tumor-infiltrating CD8 T cells encountering high (F6) or low (D4) affinity tumor antigen.
2021-12-11 | GSE141816 | GEO
Project description:TCR affinity defines tumor-specific CD8 T cell differentiation and dysfunction
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Project description:TCR affinity defines tumor-specific CD8 T cell differentiation and dysfunction [RNA-seq]
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Project description:TCR affinity defines tumor-specific CD8 T cell differentiation and dysfunction [ATAC-seq]
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Project description:Developmental checkpoints in stem/progenitor cells are critical to the determination, commitment and differentiation into distinct lineages. Cancer cells often retain expression of lineage-specific checkpoint proteins, but their potential impact in cancer remains elusive. T lymphocytes mature in the thymus following a highly orchestrated developmental process that entails the successive rearrangements and expression of T-cell receptor (TCR) genes. Low affinity recognition of self-peptide/MHC complexes (self-pMHC) presented by thymic epithelial cells by the TCR of CD4+CD8+ (DP) cortical thymocytes transduces positive selection signals that ultimately shape the developing T cell repertoire. DP thymocytes not receiving these signals die by lack of stimulation whereas those that recognize self-pMHC with high affinity undergo TCR-mediated apoptosis and negative selection. In T-cell acute lymphoblastic leukaemia (T-ALL), leukaemic transformation of maturating thymocytes results from the acquisition of multiple genetic and epigenetic alterations in oncogenes and tumour suppressor genes, that disrupt the normal regulatory circuits and drive clonal expansion of differentiation-arrested lymphoblasts. We show here that TCR triggering by negatively-selecting self-pMHC prevented T-ALL development and leukaemia maintenance in mice. Induction of TCR signalling by high affinity self-pMHC or treatment with monoclonal antibodies to the CD3 signalling chain (anti-CD3) caused massive leukaemic cell death and a gene expression program resembling that of thymocyte negative selection. Importantly, anti-CD3 treatment hampered leukaemogenesis in mice transplanted with either mouse or patient-derived T-ALLs. These data provide a rationale for targeted therapy based on anti-CD3 treatment of T-ALL patients and demonstrate that endogenous developmental checkpoint proteins are amenable to therapeutic intervention in cancer cells. Gene expression data from four culture conditions was performed for the following cells: ALL-SIL-TCRα/β-GFP co-cultured on OP9-DL1 for 48 h, ALL-SIL-TCRα/β-GFP without co-culture, ALL-SIL cells transduced with TLX shRNA (sh-TLX), and ALL-SIL transduced with sh-control vectors. All conditions are performed in two replicates.
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Project description:Most naturally occurring major histocompatibility class I restricted T cell receptors (TCRs) that target over-expressed tumor-associated self-antigens (TAAs) are of low avidity due to selection and tolerance in the host and are CD8 co-receptor dependent. Adoptive T cell transfer with TCR-engineered T cells thus rely on the function of CD8+ T cells and do not exploit beneficial CD4+ T cell functions. Hence, we developed a novel strategy that combines expression of a TAA-specific low-avidity TCR with the CD8ab co-receptor and explored the properties of purified transgenic CD8+ and CD4+ T cells separately, in vitro and in vivo. We found that CD8ab co-transfer enhanced TCR+ CD8+ T cell function by increasing their serial tumor killing capacity, indicating that limited availability of endogenous CD8 co-receptors impedes full deployment of their functional potential. Engineered CD4+ T cells were efficiently reprogrammed into hybrid multifunctional cytotoxic and helper T cells at the single-cell level: they recognized and killed cells expressing the cognate class I restricted tumor antigen, became serial killers, produced mostly TH1 and preserved some TH2 cytokines, and showed superior anti-tumor function in vivo in a leukemia xenograft model. CD8ab co-transfer restored the TCR-pMHC interaction in CD4+ T cells and enhanced early TCR signaling events. Single-cell RNA-seq profiling suggests that co-transferred CD4+ T cells acquired a cytotoxic gene expression program and at the same time retained CD4 lineage specific features. In conclusion, we present a novel approach that allows us to (1) enhance the function of TCR-transgenic CD8+ T cells and (2) to manufacture class I pMHC targeted hybrid cytotoxic and helper T cells with both CD8+ and CD4+ T cell functions readily available at the single-cell level.
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Project description:Affinity and dose of T cell receptor (TCR) interaction with antigens govern the magnitude of CD4+ T cell responses, but questions remain regarding the quantitative translation of TCR engagement into downstream signals. We find that while the response of CD4+ T cells to antigenic stimulation is bimodal, activated cells exhibit analog responses proportional to signal strength. Gene expression output reflects TCR signal strength, providing a signature of T cell activation. Expression changes rely on a pre-established enhancer landscape and quantitative acetylation at AP-1 binding sites. Finally, we show that graded expression of activation genes depends on ERK pathway activation, suggesting that an ERK-AP-1 axis translates TCR signal strength into proportional activation of enhancers and genes essential for T cell function. CD4+ T cells from transgenic AND mice were sequenced under the conditions indicated. Replicates are included for each type of data (RNA-Seq, ChIP-Seq), and are numbered accordingly. The No Peptide condition serves as the untreated control for the peptide-treated samples, and inputs are provided for ChIP-Sequencing samples.
2016-06-01 | E-GEOD-69545 | biostudies-arrayexpress
Project description:Immune system threat detection hinges on T cells’ ability to perceive varying peptide major-histocompatibility complex (pMHC) antigens. As the Erk and NFAT pathways link T cell receptor engagement to gene regulation, their signaling dynamics may convey information about pMHC inputs. To test this idea, we developed a dual reporter mouse strain and a quantitative imaging assay that, together, enable simultaneous monitoring of Erk and NFAT dynamics in live T cells over day-long timescales as they respond to varying pMHC inputs. Both pathways initially activate uniformly across various pMHC inputs, but diverge only over longer (9+ hrs) timescales, enabling independent encoding of pMHC affinity and dose. These late signaling dynamics are decoded via multiple temporal and combinatorial mechanisms to generate pMHC-specific transcriptional responses. Our findings underscore the importance of long timescale signaling dynamics in antigen perception, and establish a framework for understanding T cell responses under diverse contexts.
2023-09-06 | GSE242494 | GEO
Project description:Immune system threat detection hinges on T cells’ ability to perceive varying peptide major-histocompatibility complex (pMHC) antigens. As the Erk and NFAT pathways link T cell receptor engagement to gene regulation, their signaling dynamics may convey information about pMHC inputs. To test this idea, we developed a dual reporter mouse strain and a quantitative imaging assay that, together, enable simultaneous monitoring of Erk and NFAT dynamics in live T cells over day-long timescales as they respond to varying pMHC inputs. Both pathways initially activate uniformly across various pMHC inputs, but diverge only over longer (9+ hrs) timescales, enabling independent encoding of pMHC affinity and dose. These late signaling dynamics are decoded via multiple temporal and combinatorial mechanisms to generate pMHC-specific transcriptional responses. Our findings underscore the importance of long timescale signaling dynamics in antigen perception, and establish a framework for understanding T cell responses under diverse contexts.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2021-12-09 | GSE141818 | GEO