Gene expression profile of T cell after TCR stimulation with or without PD-1 engagement
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PROVIDER: PRJNA471086 | ENA |
REPOSITORIES: ENA
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Project description:Gene expression profile of T cell after TCR stimulation with or without PD-1 engagement was measured by cap analysis of gene expression (CAGE). This experiment provided insight into how PD-1 modulates gene expression.
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Project description:Comparison of gene expression changes in CD4+CD8+ thymocytes following engagement of TCR with anti-Valpha or Vbeta antibodies Keywords: parallel sample
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Project description:Durability of an antitumor immune response is mediated in part by the persistence of progenitor exhausted CD8 T cells (Tpex). Tpex serve as a source for the pool of effector T cells, and in the absence of their cognate antigen, they are able to preserve their quantity through a process of self-renewal. However, it remains unknown how TCR engagement impacts the self-renewal capacity of Tpex in settings of continued antigen exposure. Here, we used a Lewis lung carcinoma model that elicits an optimal or attenuated TCR signal in CD8 T cells to investigate its effect on Tpex persistence during tumor development. Longitudinal phenotyping and single-cell transcriptomics of tumor-specific T cells revealed that formation of the Tpex reservoir in tumor-draining lymph nodes, and its subsequent replenishment of intratumoral Tpex, is dependent on optimal TCR engagement. Notably, adoptive transfer of optimally primed Tpex into a tumor setting with attenuated TCR stimulation significantly accelerates their terminal differentiation, contrasting to the sustained self-renewal occuring with optimal TCR stimulation. This TCR-reinforced Tpex development and self-renewal is coupled to proximal positioning to dendritic cell niches and epigenetic imprinting that involves increased chromatin accessibility at Egr2 and Tcf1 target loci. Collectively, our study highlights the critical role of TCR engagement in sustaining Tpex during tumor progression
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Project description:Durability of an antitumor immune response is mediated in part by the persistence of progenitor exhausted CD8 T cells (Tpex). Tpex serve as a source for the pool of effector T cells, and in the absence of their cognate antigen, they are able to preserve their quantity through a process of self-renewal. However, it remains unknown how TCR engagement impacts the self-renewal capacity of Tpex in settings of continued antigen exposure. Here, we used a Lewis lung carcinoma model that elicits an optimal or attenuated TCR signal in CD8 T cells to investigate its effect on Tpex persistence during tumor development. Longitudinal phenotyping and single-cell transcriptomics of tumor-specific T cells revealed that formation of the Tpex reservoir in tumor-draining lymph nodes, and its subsequent replenishment of intratumoral Tpex, is dependent on optimal TCR engagement. Notably, adoptive transfer of optimally primed Tpex into a tumor setting with attenuated TCR stimulation significantly accelerates their terminal differentiation, contrasting to the sustained self-renewal occuring with optimal TCR stimulation. This TCR-reinforced Tpex development and self-renewal is coupled to proximal positioning to dendritic cell niches and epigenetic imprinting that involves increased chromatin accessibility at Egr2 and Tcf1 target loci. Collectively, our study highlights the critical role of TCR engagement in sustaining Tpex during tumor progression
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Project description:Comparison of gene expression changes in CD4+CD8+ thymocytes following engagement of TCR with anti-Valpha or Vbeta antibodies
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Project description:T cell coinhibitory immune checkpoints, such as PD-1 or BTLA, are bona fide targets in cancer therapy. Here we used a human T cell reporter line to measure transcriptome changes mediated by PD-1 and BTLA induced signalling. TCR/CD3 stimulation resulted in the upregulation of a large number of genes but also repressed a similar number of transcripts. PD-1 and BTLA signals attenuated transcriptomics changes mediated by TCR/CD3 signalling: upregulated genes tended to be suppressed and the expression of a significant number of downregulated genes was higher when PD-1 or BTLA signalling took place. BTLA was a significantly stronger attenuator of TCR/CD3 induced transcriptome changes than PD-1. A strong overlap between genes that were regulated indicated quantitative rather than qualitative differences between these receptors. In line with their function as attenuator of TCR/CD3 mediated changes we found strongly regulated genes to be prime targets of PD-1 and BTLA signalling.
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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.
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