Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations
Alexandra H. Mandarano, … , C. Gunnar Gottschalk, Maureen R. Hanson
Alexandra H. Mandarano, … , C. Gunnar Gottschalk, Maureen R. Hanson
Published December 12, 2019
Citation Information: J Clin Invest. 2020;130(3):1491-1505. https://doi.org/10.1172/JCI132185.
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Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and postexertional malaise. There is little known about the metabolism of specific immune cells in patients with ME/CFS. To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 patients with ME/CFS and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism and plasma cytokines. We found that ME/CFS CD8+ T cells had reduced mitochondrial membrane potential compared with those from healthy controls. Both CD4+ and CD8+ T cells from patients with ME/CFS had reduced glycolysis at rest, whereas CD8+ T cells also had reduced glycolysis following activation. Patients with ME/CFS had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from correlations seen in healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.

Authors

Alexandra H. Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L. Peterson, Marco Maynard, C. Gunnar Gottschalk, Maureen R. Hanson

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Figure 1

ME/CFS CD8+ T cell proton leak and ATP production are reduced compared with healthy control samples.

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ME/CFS CD8+ T cell proton leak and ATP production are reduced compared w...
(A) Resting mitochondrial respiration parameters for healthy control and ME/CFS CD4+ T cells, including nonmitochondrial respiration (n = 24 healthy control samples; n = 23 ME/CFS samples [n = 24/23]), basal respiration (n = 24/23), maximal respiration (n = 24/23), proton leak (n = 11/10), ATP production (n = 11/10), and spare respiratory capacity (n = 24/23). (B) Mitochondrial respiration parameters for healthy control and ME/CFS CD4+ T cells after overnight stimulation with anti-CD3/anti-CD28 and IL-2, including nonmitochondrial respiration (n = 12/11), basal respiration (n = 12/11), maximal respiration (n = 11/11), proton leak (n = 7/7), ATP production (n = 7/7), and spare respiratory capacity (n = 11/11). (C) Resting mitochondrial respiration parameters for healthy control and ME/CFS CD8+ T cells, including nonmitochondrial respiration (n = 20/22), basal respiration (n = 20/22), maximal respiration (n = 19/21), proton leak (n = 8/12), ATP production (n = 8/12), and spare respiratory capacity (n = 19/21). (D) Mitochondrial respiration parameters for healthy control and ME/CFS CD8+ T cells after stimulation, including nonmitochondrial respiration (n = 15/11), basal respiration (n = 15/11), maximal respiration (n = 15/11), proton leak (n = 8/8), ATP production (n = 8/8), and spare respiratory capacity (n = 15/11). Box plots represent the median (middle line) and 25th and 75th quartiles (bottom and top edges of box). Whiskers represent 1.5 times the IQR and outliers are defined as values beyond whiskers. *P < 0.05 by Wilcoxon rank-sum test.