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Transcriptional reprogramming primes CD8+ T cells towards exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [RNA-seq]

ABSTRACT: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME) is a severe, debilitating disease, with mounting evidence pointing to immune dysregulation as a key contributor to pathophysiology. To characterize the gene regulatory state underlying dysregulation of T cells in ME, we performed multiomic analysis of distinct subsets by integrating single-cell RNA-seq, RNA-seq and ATAC-seq, and further analyzed CD8+ T cell subpopulations following symptom provocation. Certain subsets of CD8+ T cells, as well as certain innate lineages of T cells, displayed the most pronounced dysregulation in ME. We observed upregulation of key transcription factors associated with T cell exhaustion in CD8+ T cell effector memory subsets, as well as an altered chromatin landscape and metabolic reprogramming consistent with an exhausted immune cell state. To validate these observations, we analyzed expression of exhaustion markers using flow cytometry, detecting a higher frequency of exhaustion-associated transcription factors, and supporting a novel state of immune dysregulation in ME, which may ultimately provide a basis for future therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268212 | GEO | 2024/11/11

REPOSITORIES: GEO

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Transcriptional reprogramming primes CD8+ T cells towards exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [ATAC-seq]

Project description:Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME) is a severe, debilitating disease, with mounting evidence pointing to immune dysregulation as a key contributor to pathophysiology. To characterize the gene regulatory state underlying dysregulation of T cells in ME, we performed multiomic analysis of distinct subsets by integrating single-cell RNA-seq, RNA-seq and ATAC-seq, and further analyzed CD8+ T cell subpopulations following symptom provocation. Certain subsets of CD8+ T cells, as well as certain innate lineages of T cells, displayed the most pronounced dysregulation in ME. We observed upregulation of key transcription factors associated with T cell exhaustion in CD8+ T cell effector memory subsets, as well as an altered chromatin landscape and metabolic reprogramming consistent with an exhausted immune cell state. To validate these observations, we analyzed expression of exhaustion markers using flow cytometry, detecting a higher frequency of exhaustion-associated transcription factors, and supporting a novel state of immune dysregulation in ME, which may ultimately provide a basis for future therapies.

2024-11-11 | GSE268223 | GEO

Transcriptional reprogramming primes CD8+ T cells towards exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [RNA-seq]

Project description:Transcriptional reprogramming primes CD8+ T cells towards exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [RNA-seq]

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Transcriptional reprogramming primes CD8+ T cells towards exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [ATAC-seq]

Project description:Transcriptional reprogramming primes CD8+ T cells towards exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [ATAC-seq]

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Deep phenotyping of Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [Protein]

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Deep phenotyping of Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [RNA-Seq]

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Project description:In patients with pancreatic ductal adenocarcinoma (PDAC), we show that response to radiation therapy (RT) is characterized by increased IL2R and IL2R expression, decreased ILR2 and exhaustion markers. The bispecific PD-1-targeted IL-2 variant (IL2v) immunocytokine with engineered IL-2 cis-targeted to PD-1 and abolished IL2R binding targets the activation of tumor-antigen specific T cells while rescuing them from Treg suppression. Using aPD1-IL2v in orthotopic PDAC KPC-driven tumor models, we show marked improvement in local and metastatic survival along with profound increase in tumor-infiltrating polyfunctional CD8 T cell subsets with a transcriptionally and metabolically active phenotype, and preferential activation of antigen-specific CD8 T cells. In combination with single dose RT, aPD1-IL2v treatment results in a robust, durable expansion of polyfunctional CD8 T cells, T cell stemness, tumor-specific memory immune response, NK cell activation, and decreased Tregs. These data show that the novel aPD1-IL2v, leads to profound local and distant response in PDAC.

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Identification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-associated DNA methylation patterns

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