Tag: T-cell exhaustion

Circulating cell-free RNA signatures for the characterization and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

People living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) experience heterogeneous and debilitating symptoms that lack sufficient biological explanation, compounded by the absence of accurate, noninvasive diagnostic tools. To address these challenges, we explored circulating cell-free RNA (cfRNA) as a blood-borne bioanalyte to monitor ME/CFS. cfRNA is released into the bloodstream during cellular turnover and reflects dynamic changes in gene expression, cellular signaling, and tissue-specific processes.

We profiled cfRNA in plasma by RNA sequencing for 93 ME/CFS cases and 75 healthy sedentary controls, then applied machine learning to develop diagnostic models and advance our understanding of ME/CFS pathobiology. A generalized linear model with least absolute shrinkage selector operator regression trained on condition-specific signatures achieved a test-set AUC of 0.81 and an accuracy of 77%.

Immune cfRNA deconvolution revealed differences in platelet-derived cfRNA between cases and controls, as well as elevated levels of plasmacytoid dendritic, monocyte, and T cell-derived cfRNA in ME/CFS. Biological network analysis further implicated immune dysfunction in ME/CFS, with signatures of cytokine signaling and T cell exhaustion. These findings demonstrate the utility of RNA liquid biopsy as a minimally invasive tool for unraveling the complex biology behind chronic illnesses.

Source: Gardella AE, Eweis-LaBolle D, Loy CJ, Belcher ED, Lenz JS, Franconi CJ, Scofield SY, Grimson A, Hanson MR, De Vlaminck I. Circulating cell-free RNA signatures for the characterization and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2025 Aug 19;122(33):e2507345122. doi: 10.1073/pnas.2507345122. Epub 2025 Aug 11. PMID: 40789036. https://pubmed.ncbi.nlm.nih.gov/40789036/

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

Abstract:

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.

Source: Iu DS, Maya J, Vu LT, Fogarty EA, McNairn AJ, Ahmed F, Franconi CJ, Munn PR, Grenier JK, Hanson MR, Grimson A. Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2024 Dec 10;121(50):e2415119121. doi: 10.1073/pnas.2415119121. Epub 2024 Dec 2. PMID: 39621903. https://www.pnas.org/doi/10.1073/pnas.2415119121 (Full text)

Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome

Abstract:

A substantial number of patients recovering from acute SARS-CoV-2 infection present serious lingering symptoms, often referred to as long COVID (LC). However, a subset of these patients exhibits the most debilitating symptoms characterized by ongoing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS).

We specifically identified and studied ME/CFS patients from two independent LC cohorts, at least 12 months post the onset of acute disease, and compared them to the recovered group (R). ME/CFS patients had relatively increased neutrophils and monocytes but reduced lymphocytes. Selective T cell exhaustion with reduced naïve but increased terminal effector T cells was observed in these patients. LC was associated with elevated levels of plasma pro-inflammatory cytokines, chemokines, Galectin-9 (Gal-9), and artemin (ARTN). A defined threshold of Gal-9 and ARTN concentrations had a strong association with LC.

The expansion of immunosuppressive CD71+ erythroid cells (CECs) was noted. These cells may modulate the immune response and contribute to increased ARTN concentration, which correlated with pain and cognitive impairment. Serology revealed an elevation in a variety of autoantibodies in LC. Intriguingly, we found that the frequency of 2B4+CD160+ and TIM3+CD160+ CD8+ T cells completely separated LC patients from the R group.

Our further analyses using a multiple regression model revealed that the elevated frequency/levels of CD4 terminal effector, ARTN, CEC, Gal-9, CD8 terminal effector, and MCP1 but lower frequency/levels of TGF-β and MAIT cells can distinguish LC from the R group. Our findings provide a new paradigm in the pathogenesis of ME/CFS to identify strategies for its prevention and treatment.

Source: Saito S, Shahbaz S, Osman M, Redmond D, Bozorgmehr N, Rosychuk RJ, Lam G, Sligl W, Cohen Tervaert JW, Elahi S. Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome. J Autoimmun. 2024 May 25;147:103267. doi: 10.1016/j.jaut.2024.103267. Epub ahead of print. PMID: 38797051. https://www.sciencedirect.com/science/article/pii/S089684112400101X (Full text)

Sex differences in symptomatology and immune profiles of Long COVID

Abstract:

Strong sex differences in the frequencies and manifestations of Long COVID (LC) have been reported with females significantly more likely than males to present with LC after acute SARS-CoV-2 infection1-7. However, whether immunological traits underlying LC differ between sexes, and whether such differences explain the differential manifestations of LC symptomology is currently unknown.

Here, we performed sex-based multi-dimensional immune-endocrine profiling of 165 individuals8 with and without LC in an exploratory, cross-sectional study to identify key immunological traits underlying biological sex differences in LC.

We found that female and male participants with LC experienced different sets of symptoms, and distinct patterns of organ system involvement, with female participants suffering from a higher symptom burden. Machine learning approaches identified differential sets of immune features that characterized LC in females and males. Males with LC had decreased frequencies of monocyte and DC populations, elevated NK cells, and plasma cytokines including IL-8 and TGF-β-family members.

Females with LC had increased frequencies of exhausted T cells, cytokine-secreting T cells, higher antibody reactivity to latent herpes viruses including EBV, HSV-2, and CMV, and lower testosterone levels than their control female counterparts. Testosterone levels were significantly associated with lower symptom burden in LC participants over sex designation.

These findings suggest distinct immunological processes of LC in females and males and illuminate the crucial role of immune-endocrine dysregulation in sex-specific pathology.

Source: Julio Silva, Takehiro Takahashi, Jamie Wood, Peiwen Lu, Sasha Tabachnikova, Jeffrey Gehlhausen, Kerrie Greene, Bornali Bhattacharjee, Valter Silva Monteiro, Carolina Lucas, Rahul Dhodapkar, Laura Tabacof, Mario Pena-Hernandez, Kathy Kamath, Tianyang Mao, Dayna Mccarthy, Ruslan Medzhitov, David van Dijk, Harlan Krumholz, Leying Guan, David Putrino, Akiko Iwasaki. Sex differences in symptomatology and immune profiles of Long COVID. medRxiv 2024.02.29.24303568; doi: https://doi.org/10.1101/2024.02.29.24303568 https://www.medrxiv.org/content/10.1101/2024.02.29.24303568v1 (Full study available as PDF file)

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

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.
Source: Maya J. Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International Journal of Molecular Sciences. 2023; 24(15):11937. https://doi.org/10.3390/ijms241511937 https://www.mdpi.com/1422-0067/24/15/11937 (Full text)