Epigenetic reprogramming of CD8+ T cell populations drives exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe, debilitating disease with striking similarities to long-COVID/PASC, but its etiology remains unclear. Mounting evidence implicates immune dysfunction as a potential cause for ME/CFS. We previously reported metabolic changes in ME/CFS CD8+ T cells, including increased fatty acid oxidation, decreased glycolysis, and reduced mitochondrial membrane potential - features commonly found in exhausted T cells. To comprehensively characterize the gene regulatory state underlying potential transcriptional dysregulation, we first re-analyzed a single cell transcriptomic atlas of ME/CFS by reclassifying CD8+ T cells, where we found that various clusters upregulated exhaustion-associated genes. We then generated high resolution profiles of gene expression and chromatin accessibility in effector memory (TEM) and naïve CD8+ T cells by RNA-seq and ATAC-seq at baseline and further analyzed different CD8+ subsets following symptom provocation. We observed in ME/CFS TEM upregulation of key transcription factors associated with exhaustion and downregulation of genes controlling key metabolic activities, as well as an altered chromatin landscape consistent with exhaustion programs, while ME/CFS TN displayed a potential loss of naïve identity. Our dataset serves as an important resource for understanding ME/CFS pathology and supports a novel state of immune dysregulation in ME/CFS which may offer new treatment options.