Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jul 26;24(15):11937.
doi: 10.3390/ijms241511937.

Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Jessica Maya  1
Affiliations
Review

Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Jessica Maya. Int J Mol Sci. .

Abstract

Millions globally suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The inflammatory symptoms, illness onset, recorded outbreak events, and physiological variations provide strong indications that ME/CFS, at least sometimes, has an infectious origin, possibly resulting in a chronic unidentified viral infection. Meanwhile, studies exposing generalized metabolic disruptions in ME/CFS have stimulated interest in isolated immune cells with an altered metabolic state. As the metabolism dictates the cellular function, dissecting the biomechanics of dysfunctional immune cells in ME/CFS can uncover states such as exhaustion, senescence, or anergy, providing insights into the consequences of these phenotypes in this disease. Despite the similarities that are seen metabolically between ME/CFS and other chronic viral infections that result in an exhausted immune cell state, immune cell exhaustion has not yet been verified in ME/CFS. This review explores the evidence for immunometabolic dysfunction in ME/CFS T cell and natural killer (NK) cell populations, comparing ME/CFS metabolic and functional features to dysfunctional immune cell states, and positing whether anergy, exhaustion, or senescence could be occurring in distinct immune cell populations in ME/CFS, which is consistent with the hypothesis that ME/CFS is a chronic viral disease. This comprehensive review of the ME/CFS immunometabolic literature identifies CD8+ T cell exhaustion as a probable contender, underscores the need for further investigation into the dysfunctional state of CD4+ T cells and NK cells, and explores the functional implications of molecular findings in these immune-cell types. Comprehending the cause and impact of ME/CFS immune cell dysfunction is critical to understanding the physiological mechanisms of ME/CFS, and developing effective treatments to alleviate the burden of this disabling condition.

Keywords: NK cells; T cell exhaustion; T cells; chronic fatigue syndrome; immune cell dysfunction; immunometabolism; myalgic encephalomyelitis.

PubMed Disclaimer

Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Recorded outbreaks of ME/CFS during the 1900s. Documented ME/CFS outbreaks worldwide, spanning the 1930s to the 1990s, are indicated by a red dot on the map, which represents between tens and hundreds of individuals afflicted with ME/CFS during each outbreak. The tables below the map display the number of outbreaks by country, and within each decade of this timeline [18,19,20,21,22].
Figure 2
Figure 2
Metabolism in the NK cells and T cells during the quiescence, activation, and memory states. Resting lymphocytes predominantly rely on fatty acid oxidation to maintain low energy requirements [58,59,60,61,62]. Upon activation, lymphocytes increase the substrate import, and synthesize various metabolites to support biomass for proliferation and the effector function, increasing glycolysis, OXPHOS, and fatty acid synthesis, while reducing fatty acid oxidation [58,59,60,61,62,63,64,65,66,67]. However, metabolic shifts can differ for different immune cell populations. For example, glutaminolysis and one-carbon metabolism may not be required for NK cell activation, while Tregs have been found to rely on fatty acid oxidation, rather than glycolysis, to balance the immune response [68,69,70,71]. After the infection clearance, memory cells upregulate fatty acid oxidation, to sustain themselves for potential reactivation [59,72].
Figure 3
Figure 3
Integrated sequential diagram of the potential T cell dysfunction and correlated metabolic dynamics during chronic antigen exposure. This diagram depicts a T cell throughout the differentiation stages, and the altered phenotypes that can occur at each stage (in red), with a vertical gradient that illustrates the hypometabolic states at the top, and the hypermetabolic states at the bottom [97,114,115]. The legend at the top left denotes foreign antigen exposure (dark green circles), seen in cancer and chronic viral infections, and self-antigen exposure (light green circles), seen in autoimmunity and cancers [112,114,115]. The two phenotypes at the bottom, self-ignorance- and self-tolerance-induced cell death, are regulatory checkpoints that enforce T cell tolerance, and are typically described as dysfunctional if they do not occur within the proper context; the breakdown of these mechanisms can cause an autoimmune response [114,115,116,117]. Anergy, another tolerogenic response, is a hyporesponsive state that occurs following antigen exposure, and is driven by a deficient co-stimulation in the T cell receptors [112]. Anergic cells are in a hypometabolic state during chronic viral infections and cancer, exhibiting a decreased effector function and proliferation; however, within the context of self-antigens and autoimmunity, anergy can help prevent T cell pathogenicity before the effector stage begins, and the breakdown of anergic mechanisms can lead to an autoimmune response [55,112]. In effector cells, exhaustion and senescence can both limit cell responses, but through different mechanisms. While both states can be hypometabolic, with a low proliferative capacity, senescent cells are more widespread across the disease and metabolic capabilities, with the ability to maintain some level of effector function [112,118,119,120,121].
Figure 4
Figure 4
The surface markers, functional characteristics, transcription factors, and metabolic dynamics associated with T cell anergy, exhaustion, and senescence. While T cell anergy, exhaustion, and senescence have some overlapping features, these phenotypes differ in their transcriptional landscapes and mechanisms of action, and the metabolic switching that drives these states. These states can exist in both CD4+ and CD8+ T cells; however, anergy is more commonly associated with CD4+ T cells, while exhaustion is typically linked to CD8+ T cells, which is what is represented in this figure [136,137,138,140,141]. Of note, the middle panel of this figure illustrates the transcription factor dynamics in exhausted T cells, displaying the variable expression dependent on the stage of exhaustion; for example, TCF-1 plays a significant role during the progenitor stages of T cell exhaustion [142]. The senescent state portrayed here represents both the CD4+ and CD8+ T cells. However, research indicates that CD4+ T cells exhibit a greater resistance to aging than CD8+ T cells, due to their higher metabolic diversity, including an enhanced lipid and glucose uptake [143]. This flexibility allows CD4+ T cells a reduced senescence susceptibility, and slightly improved proliferative capabilities upon becoming senescent [143].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Hanson M.R., Germain A. Letter to the Editor of Metabolites. Metabolites. 2020;10:216. doi: 10.3390/metabo10050216. - DOI - PMC - PubMed
    1. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Board on the Health of Select Populations. Institute of Medicine . Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. National Academies Press; Washington, DC, USA: 2015. The National Academies Collection: Reports funded by National Institutes of Health. - PubMed
    1. Chu L., Valencia I.J., Garvert D.W., Montoya J.G. Onset patterns and course of myalgic encephalomyelitis/chronic fatigue syndrome. Front. Pediatr. 2019;7:12. doi: 10.3389/fped.2019.00012. - DOI - PMC - PubMed
    1. Jason L.A., Porter N., Brown M., Anderson V., Brown A., Hunnell J., Lerch A. CFS: A Review of Epidemiology and Natural History Studies. Bull. IACFS/ME. 2009;17:88–106. - PMC - PubMed
    1. Jason L.A., Sunnquist M., Brown A., Evans M., Vernon S.D., Furst J., Simonis V. Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis. Fatigue. 2014;2:40–56. doi: 10.1080/21641846.2013.862993. - DOI - PMC - PubMed
-