Transcriptional reprogramming primes CD8+T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome

• 成果类型: Article
• 署名作者: Iu, David S.; Maya, Jessica; Vu, Luyen T.; Fogarty, Elizabeth A.; Mcnairn, Adrian J.; Ahmed, Faraz; Franconi, Carl J.; Munn, Paul R.; Grenier, Jennifer K.; Hanson, Maureen R.; Grimson, Andrew
• 署名单位: Cornell University; Cornell University; Cornell University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11538
• DOI: 10.1073/pnas.2415119121
• 发表日期: 2024-12-10
• 关键词: t-cells; infection; sensitivity; signature

摘要

Myalgic encephalomyelitis/chronic fatigue syndrome (ME) is a severe, debilitating disease, with substantial evidence pointing to immune dysregulation as a key contributor to pathophysiology. To characterize the gene regulatory state underlying T cell dysregulation in ME, we performed multiomic analysis across T cell subsets by integrating single- cell RNA-seq, RNA-seq, and ATAC-seq and further analyzed CD8+ T cell subpopulations following symptom provocation. Specific subsets of CD8+ T cells, as well as certain innate 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 factors. Together, these data identify T cell exhaustion as a component of ME, a finding which may provide a basis for future therapies, such as checkpoint blockade, metabolic interventions, or drugs that target chronic viral infections.