Project description:High amount of Eomes might drive T cell exhaustion. In order to understand how Eomes contributes to exhaustion of CD8+ T cell in the TME as a transcription factor, we conducted anti-Eomes ChIPseq analysis of control OT-I cells and Eomes-overexpressing OT-I cells.
Project description:High amount of Eomes might drive T cell exhaustion. In order to understand how Eomes contributes to exhaustion of CD8+ T cell in the TME, we conducted transcriptional analysis of control OT-I cells and Eomes-overexpressing OT-I cells
Project description:Memory CD8+ T cells have the ability to provide lifelong immunity against pathogens. Although memory features generally arise after challenge with a foreign antigen, naïve CD8 single positive (SP) thymocytes may acquire phenotypic and functional characteristics of memory cells in response to cytokines such as interleukin-4. This process is associated with the induction of the T-box transcription factor Eomesodermin (EOMES). However, the underlying molecular mechanisms remain ill-defined. Using epigenomic profiling, we show that these innate memory CD8SP cells acquire only a portion of the active enhancer repertoire of conventional memory cells. This reprograming is secondary to EOMES recruitment, mostly to RUNX3-bound enhancers. Furthermore, EOMES is found within chromatin-associated complexes containing BRG1 and promotes the recruitment of this chromatin remodelling factor. Also, the in vivo acquisition of EOMES-dependent program is BRG1-dependent. In conclusion, our results support a strong epigenetic basis for the EOMES-driven establishment of CD8+ T cell innate memory program.
Project description:The coinhibitory PD-1 signalling pathway plays a major role in the context of tumor-specific T cell responses. Conversely, it also contributes to the maintenance of peripheral tolerance as patients receiving anti-PD-1 treatment are prone to developing immune-related adverse events. Yet, the physiological role of the PD-1/PDL-1 axis in T cell homeostasis is still poorly understood. Herein, we show that under steady-state conditions, the absence of PD-1 signaling led to a preferential expansion of CD8+ T cells in the liver. These cells exhibited an oligoclonal TCR repertoire and a terminally differentiated exhaustion profile with high levels of the transcription factors TOX and EOMES. Using loss- or gain-of-function strategies, we could demonstrate that EOMES was required for the clonal expansion and acquisition of this differentiation program. Furthermore, single cell transcriptomics coupled to TCR repertoire analysis strongly supported the notion that these cells arise locally from liver-resident memory CD8 T cells. With these results, we uncovered an unexpected role for PD-1 signaling in liver memory T cell homeostasis.
Project description:The coinhibitory PD-1 signalling pathway plays a major role in the context of tumor-specific T cell responses. Conversely, it also contributes to the maintenance of peripheral tolerance as patients receiving anti-PD-1 treatment are prone to developing immune-related adverse events. Yet, the physiological role of the PD-1/PDL-1 axis in T cell homeostasis is still poorly understood. Herein, we show that under steady-state conditions, the absence of PD-1 signaling led to a preferential expansion of CD8+ T cells in the liver. These cells exhibited an oligoclonal TCR repertoire and a terminally differentiated exhaustion profile with high levels of the transcription factors TOX and EOMES. Using loss- or gain-of-function strategies, we could demonstrate that EOMES was required for the clonal expansion and acquisition of this differentiation program. Furthermore, single cell transcriptomics coupled to TCR repertoire analysis strongly supported the notion that these cells arise locally from liver-resident memory CD8 T cells. With these results, we uncovered an unexpected role for PD-1 signaling in liver memory T cell homeostasis.
Project description:Development, maturation, and function of CD8 T cells is regulated by transcription factor expression. Expression of the transcription factor Eomesodermin was found to be significantly increased in CD8 T cells following aOX40/aCTLA-4 immunotherapy in mice. We used microarray analysis to detail gene expression in Eomes+ and Eomes- CD8 T cells following aOX40/aCTLA-4 treatment to determin functional differences between these two populations.
Project description:CD8+ T cells isolated from HCC tissue were divided into three groups: PD1-TIM3- CD8+ TILs, exhibiting full effector function; PD1-intTIM3+ CD8+ TILs, exhibiting partial exhaustion; and PD1-hiTIM3+ CD8+ TILs, exhibiting severe exhaustion, as reflected by the differences in their ability to produce effector cytokines respectively. Transcriptome sequence analysis was performed to investigate the gene expression profile was performed.