Investigating T cell populations for immune cell exhaustion in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating disease that confines ~65 million people worldwide to a life of pain, severe exhaustion, cognitive deficits, flu-like symptoms, and postexertional malaise. We previously discovered decreased glycolysis, decreased mitochondrial membrane potential, and increased fatty acid oxidation in ME/CFS T cells. These features are commonly found in exhausted T cells, a reversible state seen in chronic viral infections that decreases cell proliferation, survival, and cytotoxicity. Our study evaluated whether exhausted T cell subsets circulate in people with ME/CFS by analyzing CD4+ and CD8+ T cells for associated inhibitory receptors and transcription factors. CD4+ and CD8+ T cells were isolated from 20 patients and 20 sedentary control blood samples and measured for ~15–17 markers at rest and after stimulation using a FACSymphony analyzer. Markers included cell population identifiers for naïve, effector, memory, regulatory, and helper T cells. We found significantly higher abundances and frequencies of transcription factors related to exhaustion in general and within PD-1+ CD8+ T cells in ME/CFS samples. Half of the ME/CFS cohort showed higher PD-1 memory CD8+ T cell frequencies than the control group. Moreover, ME/CFS CD4+ T cells exhibited higher levels of Lag3, CTLA4, and T-bet in various subsets. This research detects a novel state of immune cell dysfunction in ME/CFS that may suggest new treatment options. Supported by the Alfred P. Sloan Foundation and the National Institute of Neurological Disorders and Stroke (NINDS), NIH (U54NS105541).