Tag: CD8

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)

Post-acute sequelae of COVID-19 is characterized by diminished peripheral CD8+β7 integrin+ T cells and anti-SARS-CoV-2 IgA response

Abstract:

Several millions of individuals are estimated to develop post-acute sequelae SARS-CoV-2 condition (PASC) that persists for months after infection. Here we evaluate the immune response in convalescent individuals with PASC compared to convalescent asymptomatic and uninfected participants, six months following their COVID-19 diagnosis.

Both convalescent asymptomatic and PASC cases are characterised by higher CD8+ T cell percentages, however, the proportion of blood CD8+ T cells expressing the mucosal homing receptor β7 is low in PASC patients. CD8 T cells show increased expression of PD-1, perforin and granzyme B in PASC, and the plasma levels of type I and type III (mucosal) interferons are elevated. The humoral response is characterized by higher levels of IgA against the N and S viral proteins, particularly in those individuals who had severe acute disease.  Our results also show that consistently elevated levels of IL-6, IL-8/CXCL8 and IP-10/CXCL10 during acute disease increase the risk to develop PASC.

In summary, our study indicates that PASC is defined by persisting immunological dysfunction as late as six months following SARS-CoV-2 infection, including alterations in mucosal immune parameters, redistribution of mucosal CD8+β7Integrin+ T cells and IgA, indicative of potential viral persistence and mucosal involvement in the etiopathology of PASC.

Source: Santa Cruz A, Mendes-Frias A, Azarias-da-Silva M, André S, Oliveira AI, Pires O, Mendes M, Oliveira B, Braga M, Lopes JR, Domingues R, Costa R, Silva LN, Matos AR, Ângela C, Costa P, Carvalho A, Capela C, Pedrosa J, Castro AG, Estaquier J, Silvestre R. Post-acute sequelae of COVID-19 is characterized by diminished peripheral CD8+β7 integrin+ T cells and anti-SARS-CoV-2 IgA response. Nat Commun. 2023 Mar 30;14(1):1772. doi: 10.1038/s41467-023-37368-1. PMID: 36997530; PMCID: PMC10061413. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061413/ (Full text)

Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection

Abstract:

Background and Objectives SARS-CoV-2 infection has been associated with a syndrome of long-term neurologic sequelae that is poorly characterized. We aimed to describe and characterize in-depth features of neurologic postacute sequelae of SARS-CoV-2 infection (neuro-PASC).

Methods Between October 2020 and April 2021, 12 participants were seen at the NIH Clinical Center under an observational study to characterize ongoing neurologic abnormalities after SARS-CoV-2 infection. Autonomic function and CSF immunophenotypic analysis were compared with healthy volunteers (HVs) without prior SARS-CoV-2 infection tested using the same methodology.

Results Participants were mostly female (83%), with a mean age of 45 ± 11 years. The median time of evaluation was 9 months after COVID-19 (range 3–12 months), and most (11/12, 92%) had a history of only a mild infection. The most common neuro-PASC symptoms were cognitive difficulties and fatigue, and there was evidence for mild cognitive impairment in half of the patients (MoCA score <26). The majority (83%) had a very disabling disease, with Karnofsky Performance Status ≤80. Smell testing demonstrated different degrees of microsmia in 8 participants (66%). Brain MRI scans were normal, except 1 patient with bilateral olfactory bulb hypoplasia that was likely congenital. CSF analysis showed evidence of unique intrathecal oligoclonal bands in 3 cases (25%). Immunophenotyping of CSF compared with HVs showed that patients with neuro-PASC had lower frequencies of effector memory phenotype both for CD4+ T cells (p < 0.0001) and for CD8+ T cells (p = 0.002), an increased frequency of antibody-secreting B cells (p = 0.009), and increased frequency of cells expressing immune checkpoint molecules. On autonomic testing, there was evidence for decreased baroreflex-cardiovagal gain (p = 0.009) and an increased peripheral resistance during tilt-table testing (p < 0.0001) compared with HVs, without excessive plasma catecholamine responses.

Discussion CSF immune dysregulation and neurocirculatory abnormalities after SARS-CoV-2 infection in the setting of disabling neuro-PASC call for further evaluation to confirm these changes and explore immunomodulatory treatments in the context of clinical trials.

Source: Yair Mina, Yoshimi Enose-Akahata, Dima A. Hammoud, Anthony J. Videckis, Sandeep R. Narpala, Sarah E. O’Connell, Robin Carroll, Bob C. Lin, Cynthia Chen McMahan, Govind Nair, Lauren B. Reoma, Adrian B. McDermott, Brian Walitt, Steven Jacobson, David S. Goldstein, Bryan R. Smith, Avindra Nath. Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection. Neurol Neuroimmunol Neuroinflamm Jul 2023, 10 (4) e200097; DOI: 10.1212/NXI.0000000000200097 

Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is evidence of a potential infectious component that, along with patient symptoms and common onsets of the disease, implicates immune system dysfunction. To further our understanding of the state of ME/CFS lymphocytes, we characterized the role of fatty acids in isolated Natural Killer cells, CD4+ T cells, and CD8+ T cells in circulation and after overnight stimulation, through implicit perturbations to fatty acid oxidation.

We examined samples obtained from at least 8 and as many as 20 subjects for immune cell fatty acid characterization in a variety of experiments and found that all three isolated cell types increased their utilization of lipids and levels of pertinent proteins involved in this metabolic pathway in ME/CFS samples, particularly during higher energy demands and activation. In T cells, we characterized the cell populations contributing to these metabolic shifts, which included CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells.

We also discovered that patients with ME/CFS and healthy control samples had significant correlations between measurements of CD4+ T cell fatty acid metabolism and demographic data. These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness’s mechanism of action.

Source: Maya J, Leddy SM, Gottschalk CG, Peterson DL, Hanson MR. Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2023 Jan 19;24(3):2010. doi: 10.3390/ijms24032010. PMID: 36768336; PMCID: PMC9916395. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9916395/ (Full text)

Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2

Abstract:

Long COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple “omics” assays (CyTOF, RNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis.

Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses.

Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.

Source: Kailin Yin, Michael J. Peluso, Reuben Thomas, Min Gyoung Shin, Jason Neidleman, Xiaoyu Luo, Rebecca Hoh, Khamal Anglin, Beatrice Huang, Urania Argueta, Monica Lopez, Daisy Valdivieso, Kofi Asare, Rania Ibrahim, Ludger Ständker, Scott Lu, Sarah A. Goldberg, Sulggi A. Lee, Kara L. Lynch, J. Daniel Kelly, Jeffrey N. Martin, Jan Münch, Steven G. Deeks, Timothy J. Henrich, Nadia R. Roan. Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2. bioRxiv 2023.02.09.527892; doi: https://doi.org/10.1101/2023.02.09.527892 https://www.biorxiv.org/content/10.1101/2023.02.09.527892v1.full (Full text)

Novel clinical and immunological features associated with persistent post-acute sequelae of COVID-19 after six months of follow-up: a pilot study

Abstract:

Background: Currently, there is scant information regarding the features associated to the persistence of post-COVID-19 syndrome, which is the main aim of the present study.

Methods: A cohort study of 102 COVID-19 patients was conducted. The post-COVID-19 symptoms were assessed by a standardised questionnaire. Lymphocyte immunophenotyping was performed by flow cytometry and chemokines/cytokines, neutrophil extracellular traps, the tripartite motif 63, anti-cellular, and anti-SARS-CoV-2 IgG antibodies were addressed in serum. The primary outcome was the persistence of post-COVID-19 syndrome after six months follow-up.

Results: Thirteen patients (12.7%) developed the primary outcome and had a more frequent history of post-COVID-19 syndrome 3 months after infection onset (p = .044), increased levels of IL-1α (p = .011) and IP-10 (p = .037) and increased CD57 expression in CD8+ T cells (p = .003). There was a trend towards higher levels of IFN-γ (p = .051), IL-1β (p = .062) and IL-6 (p = .087). The history of post COVID-19 in the previous 3 months, obesity, baseline serum MIP-1α and IP-10, and CD57 expression in CD8+ T cells were independently associated with the persistence of post-COVID-19 syndrome.

Conclusion: Our data suggest an important relationship between a pro-inflammatory state mediated through metabolic pathways related to obesity and increased cellular senescence as a key element in the persistence of post-COVID-19 syndrome at six months of follow-up.

Source: Torres-Ruiz J, Lomelín-Gascón J, Lira Luna J, Vargas-Castro AS, Pérez-Fragoso A, Nuñez-Aguirre M, Alcalá-Carmona B, Absalón-Aguilar A, Balderas-Miranda JT, Maravillas-Montero JL, Mejía-Domínguez NR, Núñez-Álvarez C, Llorente L, Romero-Ramírez S, Sosa-Hernández VA, Cervantes-Díaz R, Juárez-Vega G, Meza-Sánchez D, Rull-Gabayet M, Martínez-Juárez LA, Morales L, López-López LN, Negrete-Trujillo JA, Falcón-Lezama JA, Valdez-Vázquez RR, Gallardo-Rincón H, Tapia-Conyer R, Gómez-Martín D. Novel clinical and immunological features associated with persistent post-acute sequelae of COVID-19 after six months of follow-up: a pilot study. Infect Dis (Lond). 2023 Jan 13:1-12. doi: 10.1080/23744235.2022.2158217. Epub ahead of print. PMID: 36637466. https://www.tandfonline.com/doi/full/10.1080/23744235.2022.2158217 (Full text)

SARS-CoV-2 escape from cytotoxic T cells during long-term COVID-19

Abstract:

Evolution of SARS-CoV-2 in immunocompromised hosts may result in novel variants with changed properties. While escape from humoral immunity certainly contributes to intra-host evolution, escape from cellular immunity is poorly understood. Here, we report a case of long-term COVID-19 in an immunocompromised patient with non-Hodgkin’s lymphoma who received treatment with rituximab and lacked neutralizing antibodies.

Over the 318 days of the disease, the SARS-CoV-2 genome gained a total of 40 changes, 34 of which were present by the end of the study period. Among the acquired mutations, 12 reduced or prevented the binding of known immunogenic SARS-CoV-2 HLA class I antigens. By experimentally assessing the effect of a subset of the escape mutations, we show that they resulted in a loss of as much as ~1% of effector CD8 T cell response. Our results indicate that CD8 T cell escape represents a major underappreciated contributor to SARS-CoV-2 evolution in humans.

Source: Stanevich OV, Alekseeva EI, Sergeeva M, Fadeev AV, Komissarova KS, Ivanova AA, Simakova TS, Vasilyev KA, Shurygina AP, Stukova MA, Safina KR, Nabieva ER, Garushyants SK, Klink GV, Bakin EA, Zabutova JV, Kholodnaia AN, Lukina OV, Skorokhod IA, Ryabchikova VV, Medvedeva NV, Lioznov DA, Danilenko DM, Chudakov DM, Komissarov AB, Bazykin GA. SARS-CoV-2 escape from cytotoxic T cells during long-term COVID-19. Nat Commun. 2023 Jan 10;14(1):149. doi: 10.1038/s41467-022-34033-x. PMID: 36627290; PMCID: PMC9831376. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9831376/ (Full text)

Study finds differences in energy use by immune cells in ME/CFS

Press Release: New findings published in the Journal of Clinical Investigation suggest that specific immune T cells from people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) show disruptions in the way they produce energy. The research was supported by the National Institutes of Health.

“This research gives us additional evidence for the role of the immune system in ME/CFS and may provide important clues to help us understand the mechanisms underlying this devastating disease,” said Vicky Whittemore, Ph.D., program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which partially funded the study.

ME/CFS is a severe, chronic, and debilitating disease that can cause a range of symptoms including pain, severe exhaustion, cognitive impairment, and post-exertional malaise, the worsening of symptoms after physical or mental activity. Estimates suggest that between 836,000 and 2.5 million people in the United States may be affected by ME/CFS. It is unknown what causes the disease and there are no treatments.

Research by Alexandra Mandarano and collaborators in the laboratory of Maureen Hanson, Ph.D., professor of molecular biology and genetics at Cornell University in Ithaca, New York, examined biochemical reactions involved in energy production, or metabolism, in two specific types of immune cells obtained from 45 healthy controls and 53 people with ME/CFS. Investigators focused on CD4 T cells, which alert other immune cells about invading pathogens, and CD8 T cells, which attack infected cells. Dr. Hanson’s team used state-of-the-art methods to look at energy production by the mitochondria within T cells, when the cells were in a resting state and after they had been activated. Mitochondria are biological powerhouses and create most of the energy that drives cells.

Dr. Hanson and her colleagues did not see significant differences in mitochondrial respiration, the cell’s primary energy-producing method, between healthy and ME/CFS cells at rest or after activation. However, results suggest that glycolysis, a less efficient method of energy production, may be disrupted in ME/CFS. Compared to healthy cells, CD4 and CD8 cells from people with ME/CFS had decreased levels of glycolysis at rest. In addition, ME/CFS CD8 cells had lower levels of glycolysis after activation.

“Our work demonstrates the importance of looking at particular types of immune cells that have different jobs to do, rather than looking at them all mixed together, which can hide problems specific to particular cells,” said Dr. Hanson. “Additional studies focusing on specific cell types will be important to unravel what’s gone wrong with immune defenses in ME/CFS.”

Dr. Hanson’s group also looked at mitochondrial size and membrane potential, which can indicate the health of T cell mitochondria. CD4 cells from healthy controls and people with ME/CFS showed no significant differences in mitochondrial size nor function. CD8 cells from people with ME/CFS showed decreased membrane potential compared to healthy cells during both resting and activated states.

Dr. Hanson’s team examined associations between cytokines, chemical messengers that send instructions from one cell to another, and T cell metabolism. The findings revealed different, and often opposite, patterns between healthy and ME/CFS cells, suggesting changes in the immune system. In addition, the presence of cytokines that cause inflammation unexpectedly correlated with decreased metabolism in T cells.

This study was supported in part by the NIH’s ME/CFS Collaborative Research Network, a consortium supported by multiple institutes and centers at NIH, consisting of three collaborative research centers and a data management coordinating center. The research network was established in 2017 to help advance research on ME/CFS.

“In addition to providing valuable insights into the immunology of ME/CFS, we hope that the results coming out of the collaborative research network will inspire more researchers, particularly those in the early stages of their careers, to work on this disease,” said Joseph Breen, Ph.D., section chief, Immunoregulation Section, Basic Immunology Branch, National Institute of Allergy and Infectious Diseases (NIAID), which partially funded the study.

Future research studies will examine metabolism in other subsets of immune cells. In addition, researchers will investigate ways in which changes in metabolism affect the activity of T cells.

This study was supported by NINDS grant U54NS105541, NIAID grant R21AI117595, Simmaron Research, and an anonymous private donor.

NINDS (https://www.ninds.nih.gov/) is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Reference: Mandarano et al. “Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations,” Journal of Clinical Investigation. December 12, 2019

Immunophenotyping in post-giardiasis functional gastrointestinal disease and chronic fatigue syndrome

Abstract:

BACKGROUND: A Giardia outbreak was associated with development of post-infectious functional gastrointestinal disorders (PI-FGID) and chronic fatigue syndrome (PI-CFS). Markers of immune dysfunction have given conflicting results in CFS and FGID patient populations. The aim of this study was to evaluate a wide selection of markers of immune dysfunction in these two co-occurring post-infectious syndromes.

METHODS: 48 patients, reporting chronic fatigue in a questionnaire study, were clinically evaluated five years after the outbreak and grouped according to Fukuda criteria for CFS (n=19) and idiopathic chronic fatigue (n=5) and Rome II criteria for FGIDs (n=54). 22 Giardia exposed non-fatigued individuals and 10 healthy unexposed individuals were recruited as controls. Peripheral blood lymphocyte subsets were analyzed by flow cytometry.

RESULTS: In peripheral blood we found significantly higher CD8 T-cell levels in PI-FGID, and significantly lower NK-cell levels in PI-CFS patients. Severity of abdominal and fatigue symptoms correlated negatively with NK-cell levels. A tendency towards lower T-cell CD26 expression in FGID was seen.

CONCLUSION: Patients with PI-CFS and/or PI-FGID 5 years after Giardia lamblia infection showed alterations in NK-cell and CD8-cell populations suggesting a possible immunological abnormality in these conditions. We found no significant changes in other markers examined in this well-defined group of PI-CFS and PI-FGID elicited by a gastrointestinal infection. Controlling for co-morbid conditions is important in evaluation of CFS-biomarkers.

 

Source: Hanevik K, Kristoffersen EK, Sørnes S, Mørch K, Næss H, Rivenes AC, Bødtker JE, Hausken T, Langeland N. Immunophenotyping in post-giardiasis functional gastrointestinal disease and chronic fatigue syndrome. BMC Infect Dis. 2012 Oct 14;12:258. doi: 10.1186/1471-2334-12-258. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553045/ (Full article)

 

Chronic fatigue syndrome. Immunological findings vary between populations

Comment on: Longitudinal study of outcome of chronic fatigue syndrome. [BMJ. 1994]

 

Editor,-We were interested in Andrew Wilson and colleagues’ paper investigating predictors of the long term outcome of the chronic fatigue syndrome in patients in Australia. We have investigated the association between immune activation and presumed cutaneous anergy in 68 Scottish patients with the syndrome (19 cases conformed to the Centers for Disease Control’s criteria, 18 cases had been diagnosed by a consultant, 28 cases had been diagnosed by a general practitioner, and three patients referred themselves) and 22 family contacts. We assessed delayed hypersensitivity responses (using Multitest antigens and tuberculin skin tests) and evaluated peripheral blood activation markers (CD8, CD38/ CD llb/HLA-DR) using flow cytometry. Patients were classified into three groups on the basis of current severity of illness and mobility.

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2540184/pdf/bmj00440-0055b.pdf

 

Source: Abbot NC, Spence VA, Lowe JG, Potts RC, Hassan AH, Belch JJ, Beck JS. Chronic fatigue syndrome. Immunological findings vary between populations. BMJ. 1994 May 14;308(6939):1299. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2540184/