{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T14:05:39Z","timestamp":1788444339581,"version":"build-2803163510"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":34,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS) is a debilitating but poorly-understood disease. ME\/CFS symptoms include immune system effects alongside incapacitating fatigue and post-exertional disease exacerbation. Symptom severity can range from mild to severe and whilst symptoms can fluctuate, few people fully recover.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Immunological profiles of people living with ME\/CFS were analysed by flow cytometry, focusing on cytotoxic cells, to determine whether people with mild\/moderate (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200943) or severe ME\/CFS (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200953) expressed different immunological markers. Flow cytometry data were tested for normality and the two clinical groups were compared by t-test or Mann-Whitney U-test as appropriate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      People with mild\/moderate ME\/CFS had increased expression of cytotoxic effector molecules alongside enhanced proportions of early-immunosenescence cells, determined by the CD28\n                      <jats:sup>-<\/jats:sup>\n                      CD57\n                      <jats:sup>-<\/jats:sup>\n                      phenotype, indicative of persistent viral infection. In contrast, people with severe ME\/CFS had higher proportions of activated circulating lymphocytes, determined by CD69\n                      <jats:sup>+<\/jats:sup>\n                      and CD38\n                      <jats:sup>+<\/jats:sup>\n                      expression, and expressed more pro-inflammatory cytokines, including interferon-\u03b3, tumour necrosis factor and interleukin-17, following stimulation in vitro, indicative of prolonged non-specific inflammation. These changes were consistent across different cell types including CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, mucosal associated invariant T cells and Natural Killer cells, indicating generalised altered cytotoxic responses across the innate and adaptive immune system.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These immunological differences likely reflect different disease pathogenesis mechanisms occurring in the two clinical groups, opening up opportunities for the development of prognostic markers and stratified treatments.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-025-07507-x","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T08:55:44Z","timestamp":1765356944000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Abnormal T-Cell activation and cytotoxic T-Cell frequency discriminate symptom severity in myalgic encephalomyelitis\/chronic fatigue syndrome"],"prefix":"10.1186","volume":"24","author":[{"given":"Ji-Sook","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliana","family":"Lacerda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Kingdon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ella","family":"Abken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giada","family":"Susannini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazel M.","family":"Dockrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Nacul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5653-1818","authenticated-orcid":false,"given":"Jacqueline M.","family":"Cliff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"issue":"5","key":"7507_CR1","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.3390\/jcm9051557","volume":"9","author":"F Estevez-Lopez","year":"2020","unstructured":"Estevez-Lopez F, Mudie K, Wang-Steverding X, et al. Systematic review of the epidemiological burden of myalgic Encephalomyelitis\/Chronic fatigue syndrome across Europe: current evidence and EUROMENE research recommendations for epidemiology. J Clin Med. 2020;9(5):1557.","journal-title":"J Clin Med"},{"issue":"4","key":"7507_CR2","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1007\/s41669-018-0071-6","volume":"2","author":"CC Kingdon","year":"2018","unstructured":"Kingdon CC, Bowman EW, Curran H, Nacul L, Lacerda EM. Functional status and well-being in people with myalgic Encephalomyelitis\/Chronic fatigue syndrome compared with people with multiple sclerosis and healthy controls. Pharmacoecon Open. 2018;2(4):381\u201392.","journal-title":"Pharmacoecon Open"},{"key":"7507_CR3","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1186\/1471-2458-11-402","volume":"11","author":"LC Nacul","year":"2011","unstructured":"Nacul LC, Lacerda EM, Campion P, et al. The functional status and well being of people with myalgic encephalomyelitis\/chronic fatigue syndrome and their carers. BMC Public Health. 2011;11:402.","journal-title":"BMC Public Health"},{"issue":"3","key":"7507_CR4","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1136\/archdischild-2022-324319","volume":"108","author":"AP Royston","year":"2023","unstructured":"Royston AP, Rai M, Brigden A, Burge S, Segal TY, Crawley EM. Severe myalgic encephalomyelitis\/chronic fatigue syndrome in children and young people: a British paediatric surveillance Unit study. Arch Dis Child. 2023;108(3):230\u201335.","journal-title":"Arch Dis Child"},{"key":"7507_CR5","doi-asserted-by":"publisher","first-page":"688159","DOI":"10.3389\/fmed.2021.688159","volume":"8","author":"S O\u2019Boyle","year":"2021","unstructured":"O\u2019Boyle S, Nacul L, Nacul FE, et al. A natural history of disease framework for improving the prevention, management, and research on Post-viral fatigue syndrome and other forms of myalgic Encephalomyelitis\/Chronic fatigue syndrome. Front Med (Lausanne). 2021;8:688159.","journal-title":"Front Med (Lausanne)"},{"key":"7507_CR6","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3389\/fped.2019.00012","volume":"7","author":"L Chu","year":"2019","unstructured":"Chu L, Valencia IJ, Garvert DW, Montoya JG. Onset patterns and course of myalgic Encephalomyelitis\/Chronic fatigue syndrome. Front Pediatr. 2019;7:12.","journal-title":"Front Pediatr"},{"key":"7507_CR7","doi-asserted-by":"publisher","first-page":"826","DOI":"10.3389\/fneur.2020.00826","volume":"11","author":"L Nacul","year":"2020","unstructured":"Nacul L, O\u2019Boyle S, Palla L, et al. How myalgic Encephalomyelitis\/Chronic fatigue syndrome (ME\/CFS) progresses: the natural history of ME\/CFS. Front Neurol. 2020;11:826.","journal-title":"Front Neurol"},{"issue":"2","key":"7507_CR8","doi-asserted-by":"publisher","first-page":"106","DOI":"10.3390\/healthcare9020106","volume":"9","author":"K Conroy","year":"2021","unstructured":"Conroy K, Bhatia S, Islam M, Jason LA. Homebound versus bedridden status among those with myalgic Encephalomyelitis\/Chronic fatigue syndrome. Healthcare (basel). 2021;9(2):106.","journal-title":"Healthcare (basel)"},{"issue":"1","key":"7507_CR9","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1300\/J092v11n01_02","volume":"11","author":"B Carruthers","year":"2003","unstructured":"Carruthers B, Jain AK, de Meirleir K.L., et al. Myalgic Encephalomyelitis\/Chronic fatigue syndrome: clinical working case definition, diagnostic and treatment guidelines a consensus document. J Chronic Fatigue Syndr. 2003;11(1):7\u2013115.","journal-title":"J Chronic Fatigue Syndr"},{"key":"7507_CR10","unstructured":"Carruthers B, van de Sande MI. Myalgic encephalomyelitis - adult & paediatric: international consensus primer for medical practitioners. 2012."},{"key":"7507_CR11","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1186\/1479-5876-10-88","volume":"10","author":"EW Brenu","year":"2012","unstructured":"Brenu EW, van Driel ML, Staines DR, et al. Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome\/myalgic encephalomyelitis. J Transl Med. 2012;10:88.","journal-title":"J Transl Med"},{"key":"7507_CR12","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/1479-5876-11-68","volume":"11","author":"M Curriu","year":"2013","unstructured":"Curriu M, Carrillo J, Massanella M, et al. Screening NK-, B- and T-cell phenotype and function in patients suffering from chronic fatigue syndrome. J Transl Med. 2013;11:68.","journal-title":"J Transl Med"},{"key":"7507_CR13","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.3389\/fimmu.2018.01028","volume":"9","author":"JL Rivas","year":"2018","unstructured":"Rivas JL, Palencia T, Fernandez G, Garcia M. Association of T and NK cell phenotype with the diagnosis of myalgic Encephalomyelitis\/Chronic fatigue syndrome (ME\/CFS). Front Immunol. 2018;9:1028.","journal-title":"Front Immunol"},{"issue":"1","key":"7507_CR14","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1186\/s13643-019-1202-6","volume":"8","author":"N Eaton-Fitch","year":"2019","unstructured":"Eaton-Fitch N, du Preez S, Cabanas H, Staines D, Marshall-Gradisnik S. A systematic review of natural killer cells profile and cytotoxic function in myalgic encephalomyelitis\/chronic fatigue syndrome. Syst Rev. 2019;8(1):279.","journal-title":"Syst Rev"},{"key":"7507_CR15","doi-asserted-by":"crossref","unstructured":"Karhan E, Gunter CL, Ravanmehr V, et al. Perturbation of effector and regulatory T cell subsets in myalgic Encephalomyelitis\/Chronic fatigue syndrome (ME\/CFS). 2019. https:\/\/www.biorxiv.org\/content\/10.1101\/2019.12.23.887505v1","DOI":"10.1101\/2019.12.23.887505"},{"issue":"9","key":"7507_CR16","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.1002\/jmv.24810","volume":"89","author":"P Halpin","year":"2017","unstructured":"Halpin P, Williams MV, Klimas NG, Fletcher MA, Barnes Z, Ariza ME. Myalgic encephalomyelitis\/chronic fatigue syndrome and gulf war illness patients exhibit increased humoral responses to the herpesviruses-encoded dUtpase: implications in disease pathophysiology. J Med Virol. 2017;89(9):1636\u201345.","journal-title":"J Med Virol"},{"key":"7507_CR17","doi-asserted-by":"publisher","first-page":"656692","DOI":"10.3389\/fmed.2021.656692","volume":"8","author":"JS Lee","year":"2021","unstructured":"Lee JS, Lacerda EM, Nacul L, et al. Salivary DNA loads for human herpesviruses 6 and 7 are correlated with disease phenotype in myalgic Encephalomyelitis\/Chronic fatigue syndrome. Front Med (Lausanne). 2021;8:656692.","journal-title":"Front Med (Lausanne)"},{"key":"7507_CR18","doi-asserted-by":"publisher","first-page":"796","DOI":"10.3389\/fimmu.2019.00796","volume":"10","author":"JM Cliff","year":"2019","unstructured":"Cliff JM, King EC, Lee JS, et al. Cellular immune function in myalgic Encephalomyelitis\/Chronic fatigue syndrome (ME\/CFS). Front Immunol. 2019;10:796.","journal-title":"Front Immunol"},{"issue":"1","key":"7507_CR19","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1186\/s12967-023-03958-2","volume":"21","author":"TD Querec","year":"2023","unstructured":"Querec TD, Lin JS, Chen Y, et al. Natural killer cytotoxicity in myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS): a multi-site clinical assessment of ME\/CFS (MCAM) sub-study. J Transl Med. 2023;21(1):242.","journal-title":"J Transl Med"},{"key":"7507_CR20","doi-asserted-by":"publisher","first-page":"723","DOI":"10.3389\/fimmu.2017.00723","volume":"8","author":"J Theorell","year":"2017","unstructured":"Theorell J, Bileviciute-Ljungar I, Tesi B, et al. Unperturbed cytotoxic lymphocyte phenotype and function in myalgic Encephalomyelitis\/Chronic fatigue syndrome patients. Front Immunol. 2017;8:723.","journal-title":"Front Immunol"},{"issue":"1","key":"7507_CR21","doi-asserted-by":"publisher","first-page":"5104","DOI":"10.1038\/s41467-022-32507-6","volume":"13","author":"C Kedor","year":"2022","unstructured":"Kedor C, Freitag H, Meyer-Arndt L, et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022;13(1):5104.","journal-title":"Nat Commun"},{"key":"7507_CR22","doi-asserted-by":"crossref","unstructured":"Paul BD, Lemle MD, Komaroff AL, Snyder SH. Redox imbalance links COVID-19 and myalgic encephalomyelitis\/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2021;118(34).","DOI":"10.1073\/pnas.2024358118"},{"key":"7507_CR23","doi-asserted-by":"crossref","unstructured":"Nacul LC, Mudie K, Kingdon CC, Clark TG, Lacerda EM. Hand Grip strength as a clinical biomarker for ME\/CFS and Disease severity. Front Neurol. 2018;9.","DOI":"10.3389\/fneur.2018.00992"},{"key":"7507_CR24","doi-asserted-by":"crossref","unstructured":"Nacul L, de Barros B, Kingdon CC, et al. Evidence of clinical pathology abnormalities in people with myalgic Encephalomyelitis\/Chronic fatigue syndrome (ME\/CFS) from an analytic Cross-sectional study. Diagn (Basel). 2019;9(2).","DOI":"10.3390\/diagnostics9020041"},{"issue":"34","key":"7507_CR25","doi-asserted-by":"publisher","first-page":"E7150","DOI":"10.1073\/pnas.1710519114","volume":"114","author":"JG Montoya","year":"2017","unstructured":"Montoya JG, Holmes TH, Anderson JN, et al. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci U S A. 2017;114(34):E7150\u20138.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"7507_CR26","doi-asserted-by":"crossref","unstructured":"Hornig M, Montoya JG, Klimas NG, et al. Distinct plasma immune signatures in ME\/CFS are present early in the course of illness. Sci Adv. 2015;1(1).","DOI":"10.1126\/sciadv.1400121"},{"key":"7507_CR27","doi-asserted-by":"crossref","unstructured":"Freitag H, Szklarski M, Lorenz S, et al. Autoantibodies to vasoregulative G-Protein-coupled receptors correlate with symptom severity, autonomic dysfunction and disability in myalgic Encephalomyelitis\/Chronic fatigue syndrome. J Clin Med. 2021;10(16).","DOI":"10.3390\/jcm10163675"},{"issue":"8","key":"7507_CR28","doi-asserted-by":"publisher","first-page":"e0272703","DOI":"10.1371\/journal.pone.0272703","volume":"17","author":"F Jahanbani","year":"2022","unstructured":"Jahanbani F, Maynard RD, Sing JC, et al. Phenotypic characteristics of peripheral immune cells of myalgic encephalomyelitis\/chronic fatigue syndrome via transmission electron microscopy: a pilot study. PLoS One. 2022;17(8):e0272703.","journal-title":"PLoS One"},{"issue":"12","key":"7507_CR29","first-page":"953","volume":"121","author":"K Fukuda","year":"1994","unstructured":"Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Int Chronic Fatigue Syndr Study Group. Ann Of Intern Med. 1994;121(12):953\u201359.","journal-title":"Int Chronic Fatigue Syndr Study Group. Ann Of Intern Med"},{"key":"7507_CR30","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.3389\/fneur.2018.01026","volume":"9","author":"EM Lacerda","year":"2018","unstructured":"Lacerda EM, Mudie K, Kingdon CC, Butterworth JD, O\u2019Boyle S, Nacul L. The UK ME\/CFS biobank: a disease-specific biobank for advancing clinical research into myalgic Encephalomyelitis\/Chronic fatigue syndrome. Front Neurol. 2018;9:1026.","journal-title":"Front Neurol"},{"issue":"7500","key":"7507_CR31","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/nature13160","volume":"509","author":"AJ Corbett","year":"2014","unstructured":"Corbett AJ, Eckle SB, Birkinshaw RW, et al. T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature. 2014;509(7500):361\u201365.","journal-title":"Nature"},{"issue":"7","key":"7507_CR32","doi-asserted-by":"publisher","first-page":"2711","DOI":"10.1182\/blood-2002-07-2103","volume":"101","author":"JM Brenchley","year":"2003","unstructured":"Brenchley JM, Karandikar NJ, Betts MR, et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood. 2003;101(7):2711\u201320.","journal-title":"Blood"},{"issue":"3","key":"7507_CR33","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1002\/eji.201948362","volume":"50","author":"L Pangrazzi","year":"2020","unstructured":"Pangrazzi L, Reidla J, Carmona Arana JA, et al. CD28 and CD57 define four populations with distinct phenotypic properties within human CD8(+) T cells. Eur J Immunol. 2020;50(3):363\u201379.","journal-title":"Eur J Immunol"},{"issue":"1","key":"7507_CR34","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1111\/j.1365-2567.2011.03470.x","volume":"134","author":"M Strioga","year":"2011","unstructured":"Strioga M, Pasukoniene V, Characiejus D. CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease. Immunology. 2011;134(1):17\u201332.","journal-title":"Immunology"},{"issue":"4","key":"7507_CR35","doi-asserted-by":"publisher","first-page":"1250","DOI":"10.1182\/blood-2010-08-303339","volume":"117","author":"M Dusseaux","year":"2011","unstructured":"Dusseaux M, Martin E, Serriari N, et al. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood. 2011;117(4):1250\u201359.","journal-title":"Blood"},{"key":"7507_CR36","doi-asserted-by":"crossref","unstructured":"Parrot T, Healy K, Boulouis C, et al. Expansion of donor-unrestricted MAIT cells with enhanced cytolytic function suitable for TCR redirection. JCI Insight. 2021;6(5).","DOI":"10.1172\/jci.insight.140074"},{"issue":"3","key":"7507_CR37","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1111\/j.1365-2249.1994.tb07015.x","volume":"95","author":"L Kestens","year":"1994","unstructured":"Kestens L, Vanham G, Vereecken C, et al. Selective increase of activation antigens HLA-DR and CD38 on CD4+ CD45RO+ T lymphocytes during HIV-1 infection. Clin Exp Immunol. 1994;95(3):436\u201341.","journal-title":"Clin Exp Immunol"},{"issue":"24","key":"7507_CR38","doi-asserted-by":"publisher","first-page":"11259","DOI":"10.1128\/JVI.01424-16","volume":"90","author":"A Chandele","year":"2016","unstructured":"Chandele A, Sewatanon J, Gunisetty S, et al. Characterization of human CD8 T cell responses in dengue virus-infected patients from India. J Virol. 2016;90(24):11259\u201378.","journal-title":"J Virol"},{"issue":"3","key":"7507_CR39","doi-asserted-by":"publisher","first-page":"100208","DOI":"10.1016\/j.xcrm.2021.100208","volume":"2","author":"M Koutsakos","year":"2021","unstructured":"Koutsakos M, Rowntree LC, Hensen L, et al. Integrated immune dynamics define correlates of COVID-19 severity and antibody responses. Cell Rep Med. 2021;2(3):100208.","journal-title":"Cell Rep Med"},{"issue":"6","key":"7507_CR40","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/S0092-8674(00)80702-3","volume":"100","author":"SJ Szabo","year":"2000","unstructured":"Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000;100(6):655\u201369.","journal-title":"Cell"},{"key":"7507_CR41","doi-asserted-by":"publisher","first-page":"761920","DOI":"10.3389\/fimmu.2021.761920","volume":"12","author":"C Huang","year":"2021","unstructured":"Huang C, Bi J. Expression regulation and function of T-Bet in NK cells. Front Immunol. 2021;12:761920.","journal-title":"Front Immunol"},{"key":"7507_CR42","doi-asserted-by":"publisher","first-page":"735784","DOI":"10.3389\/fpsyt.2021.735784","volume":"12","author":"I Murga","year":"2021","unstructured":"Murga I, Aranburu L, Gargiulo PA, G\u00f3mez Esteban JC, Lafuente JV. Clinical heterogeneity in ME\/CFS. A way to understand long-COVID19 fatigue. Front Psychiatry. 2021;12:735784.","journal-title":"Front Psychiatry"},{"issue":"1","key":"7507_CR43","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1186\/s12967-023-03946-6","volume":"21","author":"AW Vaes","year":"2023","unstructured":"Vaes AW, Van Herck M, Deng Q, Delbressine JM, Jason LA, Spruit MA. Symptom-based clusters in people with ME\/CFS: an illustration of clinical variety in a cross-sectional cohort. J Transl Med. 2023;21(1):112.","journal-title":"J Transl Med"},{"issue":"1","key":"7507_CR44","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s12967-021-02713-9","volume":"19","author":"TT Asprusten","year":"2021","unstructured":"Asprusten TT, Sletner L, Wyller VBB. Are there subgroups of chronic fatigue syndrome? An exploratory cluster analysis of biological markers. J Transl Med. 2021;19(1):48.","journal-title":"J Transl Med"},{"issue":"3","key":"7507_CR45","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/s13317-013-0051-x","volume":"4","author":"EW Brenu","year":"2013","unstructured":"Brenu EW, Hardcastle SL, Atkinson GM, et al. Natural killer cells in patients with severe chronic fatigue syndrome. Auto Immun Highlights. 2013;4(3):69\u201380.","journal-title":"Auto Immun Highlights"},{"key":"7507_CR46","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1186\/1479-5876-9-81","volume":"9","author":"EW Brenu","year":"2011","unstructured":"Brenu EW, van Driel ML, Staines DR, et al. Immunological abnormalities as potential biomarkers in chronic fatigue Syndrome\/Myalgic encephalomyelitis. J Transl Med. 2011;9:81.","journal-title":"J Transl Med"},{"key":"7507_CR47","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1186\/s12967-015-0653-3","volume":"13","author":"SL Hardcastle","year":"2015","unstructured":"Hardcastle SL, Brenu EW, Johnston S, et al. Longitudinal analysis of immune abnormalities in varying severities of chronic fatigue Syndrome\/Myalgic encephalomyelitis patients. J Transl Med. 2015;13:299.","journal-title":"J Transl Med"},{"issue":"50","key":"7507_CR48","doi-asserted-by":"publisher","first-page":"e2415119121","DOI":"10.1073\/pnas.2415119121","volume":"121","author":"DS Iu","year":"2024","unstructured":"Iu DS, Maya J, Vu LT, et al. Transcriptional reprogramming primes CD8+ T cells toward exhaustion in myalgic encephalomyelitis\/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2024;121(50):e2415119121.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"7507_CR49","doi-asserted-by":"publisher","first-page":"2460","DOI":"10.1111\/ajt.12937","volume":"14","author":"D Mou","year":"2014","unstructured":"Mou D, Espinosa J, Lo DJ, Kirk AD. CD28 negative T cells: is their loss our gain? Am J Transpl. 2014;14(11):2460\u201366.","journal-title":"Am J Transpl"},{"issue":"12","key":"7507_CR50","doi-asserted-by":"publisher","first-page":"e343","DOI":"10.1371\/journal.pmed.0020343","volume":"2","author":"A Isa","year":"2005","unstructured":"Isa A, Kasprowicz V, Norbeck O, et al. Prolonged activation of virus-specific CD8+T cells after acute B19 infection. PLoS Med. 2005;2(12):e343.","journal-title":"PLoS Med"},{"issue":"7","key":"7507_CR51","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.it.2009.03.013","volume":"30","author":"NP Weng","year":"2009","unstructured":"Weng NP, Akbar AN, Goronzy J. CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol. 2009;30(7):306\u201312.","journal-title":"Trends Immunol"},{"issue":"11","key":"7507_CR52","doi-asserted-by":"publisher","first-page":"2667","DOI":"10.1084\/jem.20062376","volume":"204","author":"Z Xiao","year":"2007","unstructured":"Xiao Z, Mescher MF, Jameson SC. Detuning CD8 T cells: down-regulation of CD8 expression, tetramer binding, and response during CTL activation. J Exp Med. 2007;204(11):2667\u201377.","journal-title":"J Exp Med"},{"issue":"3","key":"7507_CR53","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1046\/j.1365-2567.2003.01590.x","volume":"108","author":"A Trautmann","year":"2003","unstructured":"Trautmann A, Ruckert B, Schmid-Grendelmeier P, et al. Human CD8 T cells of the peripheral blood contain a low CD8 expressing cytotoxic\/effector subpopulation. Immunology. 2003;108(3):305\u201312.","journal-title":"Immunology"},{"key":"7507_CR54","doi-asserted-by":"crossref","unstructured":"Adamczyk M, Bartosinska J, Raczkiewicz D, et al. The expression of activation markers CD25 and CD69 increases during biologic treatment of psoriasis. J Clin Med. 2023;12(20).","DOI":"10.3390\/jcm12206573"},{"issue":"2","key":"7507_CR55","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1006\/clin.1998.4524","volume":"87","author":"A Gessl","year":"1998","unstructured":"Gessl A, Waldhausl W. Elevated CD69 expression on naive peripheral blood T-cells in hyperthyroid graves\u2019 disease and autoimmune thyroiditis: discordant effect of methimazole on HLA-DR and CD69. Clin Immunol Immunopathol. 1998;87(2):168\u201375.","journal-title":"Clin Immunol Immunopathol"},{"issue":"1","key":"7507_CR56","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s42358-019-0072-x","volume":"59","author":"TV Peixoto","year":"2019","unstructured":"Peixoto TV, Carrasco S, Botte DAC, et al. CD4(+)CD69(+) T cells and CD4(+)CD25(+)FoxP3(+) Treg cells imbalance in peripheral blood, spleen and peritoneal lavage from pristane-induced systemic lupus erythematosus (sle) mice. Adv Rheumatol. 2019;59(1):30.","journal-title":"Adv Rheumatol"},{"key":"7507_CR57","doi-asserted-by":"publisher","first-page":"102453","DOI":"10.1016\/j.jaut.2020.102453","volume":"111","author":"AM Gorabi","year":"2020","unstructured":"Gorabi AM, Hajighasemi S, Kiaie N, et al. The pivotal role of CD69 in autoimmunity. J Autoimmun. 2020;111:102453.","journal-title":"J Autoimmun"},{"issue":"3","key":"7507_CR58","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1007\/s10875-010-9506-2","volume":"31","author":"N TrehanPati","year":"2011","unstructured":"TrehanPati N, Sukriti S, Geffers R, et al. Gene expression profiles of T cells from hepatitis E virus infected patients in acute and resolving phase. J Clin Immunol. 2011;31(3):498\u2013508.","journal-title":"J Clin Immunol"},{"issue":"49","key":"7507_CR59","doi-asserted-by":"publisher","first-page":"E11513","DOI":"10.1073\/pnas.1812273115","volume":"115","author":"J Dias","year":"2018","unstructured":"Dias J, Boulouis C, Gorin JB, et al. The CD4(-)CD8(-) MAIT cell subpopulation is a functionally distinct subset developmentally related to the main CD8(+) MAIT cell pool. Proc Natl Acad Sci U S A. 2018;115(49):E11513\u201322.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"7507_CR60","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.4049\/jimmunol.2100522","volume":"208","author":"CK Vorkas","year":"2022","unstructured":"Vorkas CK, Krishna C, Li K, et al. Single-cell transcriptional profiling reveals signatures of helper, effector, and regulatory MAIT cells during homeostasis and activation. J Immunol. 2022;208(5):1042\u201356.","journal-title":"J Immunol"},{"issue":"10","key":"7507_CR61","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1038\/s41577-019-0191-y","volume":"19","author":"A Toubal","year":"2019","unstructured":"Toubal A, Nel I, Lotersztajn S, Lehuen A. Mucosal-associated invariant T cells and disease. Nat Rev Immunol. 2019;19(10):643\u201357.","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"7507_CR62","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1189\/jlb.4TA0815-391RR","volume":"100","author":"J Dias","year":"2016","unstructured":"Dias J, Sobkowiak MJ, Sandberg JK, Leeansyah E. Human MAIT-cell responses to Escherichia coli: activation, cytokine production, proliferation, and cytotoxicity. J Leukoc Biol. 2016;100(1):233\u201340.","journal-title":"J Leukoc Biol"},{"issue":"1","key":"7507_CR63","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1186\/s40001-024-01747-1","volume":"29","author":"JH Wang","year":"2024","unstructured":"Wang JH, Choi Y, Lee JS, Hwang SJ, Gu J, Son CG. Clinical evidence of the link between gut microbiome and myalgic encephalomyelitis\/chronic fatigue syndrome: a retrospective review. Eur J Med Res. 2024;29(1):148.","journal-title":"Eur J Med Res"},{"key":"7507_CR64","doi-asserted-by":"crossref","unstructured":"Vorkas CK, Wipperman MF, Li K, et al. Mucosal-associated invariant and gammadelta T cell subsets respond to initial mycobacterium tuberculosis infection. JCI Insight. 2018;3(19).","DOI":"10.1172\/jci.insight.121899"},{"issue":"12","key":"7507_CR65","doi-asserted-by":"publisher","first-page":"3061","DOI":"10.1016\/j.celrep.2019.08.054","volume":"28","author":"R Lamichhane","year":"2019","unstructured":"Lamichhane R, Schneider M, de la Harpe SM, et al. TCR- or cytokine-activated CD8(+) mucosal-associated invariant T cells are rapid polyfunctional effectors that can coordinate immune responses. Cell Rep. 2019;28(12):3061\u201376 e5.","journal-title":"Cell Rep"},{"issue":"3\u20134","key":"7507_CR66","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/s00430-019-00608-7","volume":"208","author":"van den Berg Sph","year":"2019","unstructured":"van den Berg Sph, Pardieck IN, Lanfermeijer J, et al. The hallmarks of CMV-specific CD8 T-cell differentiation. Med Microbiol Immunol. 2019;208(3\u20134):365\u201373.","journal-title":"Med Microbiol Immunol"},{"key":"7507_CR67","doi-asserted-by":"crossref","unstructured":"Hassouneh F, Goldeck D, Pera A, et al. Functional changes of T-Cell subsets with age and CMV infection. Int J Mol Sci. 2021;22(18).","DOI":"10.3390\/ijms22189973"},{"key":"7507_CR68","doi-asserted-by":"publisher","first-page":"620386","DOI":"10.3389\/fimmu.2021.620386","volume":"12","author":"W Zhang","year":"2021","unstructured":"Zhang W, Morris AB, Peek EV, et al. CMV status drives distinct trajectories of CD4+ T cell differentiation. Front Immunol. 2021;12:620386.","journal-title":"Front Immunol"},{"issue":"8","key":"7507_CR69","doi-asserted-by":"publisher","first-page":"2148","DOI":"10.1038\/s41591-024-03173-6","volume":"30","author":"Z Al-Aly","year":"2024","unstructured":"Al-Aly Z, Davis H, McCorkell L, et al. Long covid science, research and policy. Nat Med. 2024;30(8):2148\u201364.","journal-title":"Nat Med"},{"issue":"7985","key":"7507_CR70","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1038\/s41586-023-06651-y","volume":"623","author":"J Klein","year":"2023","unstructured":"Klein J, Wood J, Jaycox JR, et al. Distinguishing features of long covid identified through immune profiling. Nature. 2023;623(7985):139\u201348.","journal-title":"Nature"},{"issue":"2","key":"7507_CR71","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1038\/s41590-023-01724-6","volume":"25","author":"K Yin","year":"2024","unstructured":"Yin K, Peluso MJ, Luo X, et al. Long covid manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2. Nat Immunol. 2024;25(2):218\u201325.","journal-title":"Nat Immunol"},{"key":"7507_CR72","doi-asserted-by":"crossref","unstructured":"Vojdani A, Vojdani E, Saidara E, Maes M. Persistent SARS-CoV-2 infection, EBV, HHV-6 and other factors may contribute to inflammation and autoimmunity in long covid. Viruses. 2023;15(2).","DOI":"10.3390\/v15020400"},{"key":"7507_CR73","doi-asserted-by":"crossref","unstructured":"Eaton-Fitch N, Rudd P, Er T, Hool L, Herrero L, Marshall-Gradisnik S. Immune exhaustion in ME\/CFS and long covid. JCI Insight. 2024;9(20).","DOI":"10.1172\/jci.insight.183810"},{"issue":"1","key":"7507_CR74","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1186\/s12967-025-06146-6","volume":"23","author":"KSP Clarke","year":"2025","unstructured":"Clarke KSP, Kingdon CC, Hughes MP, et al. The search for a blood-based biomarker for myalgic Encephalomyelitis\/Chronic fatigue syndrome (ME\/CFS): from biochemistry to electrophysiology. J Transl Med. 2025;23(1):149.","journal-title":"J Transl Med"},{"issue":"1","key":"7507_CR75","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1186\/s12967-025-07203-w","volume":"23","author":"E Hunter","year":"2025","unstructured":"Hunter E, Alshaker H, Bundock O, et al. Development and validation of blood-based diagnostic biomarkers for myalgic Encephalomyelitis\/Chronic fatigue syndrome (ME\/CFS) using EpiSwitch\u00ae 3-dimensional genomic regulatory immuno-genetic profiling. J Transl Med. 2025;23(1):1048.","journal-title":"J Transl Med"},{"issue":"24","key":"7507_CR76","doi-asserted-by":"publisher","first-page":"eadn6331","DOI":"10.1126\/sciadv.adn6331","volume":"10","author":"Y Zheng","year":"2024","unstructured":"Zheng Y, Han F, Wu Z, et al. MAIT cell activation and recruitment in inflammation and tissue damage in acute appendicitis. Sci Adv. 2024;10(24):eadn6331.","journal-title":"Sci Adv"},{"issue":"5","key":"7507_CR77","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1111\/imcb.12021","volume":"96","author":"NA Gherardin","year":"2018","unstructured":"Gherardin NA, Souter MN, Koay HF, et al. Human blood MAIT cell subsets defined using MR1 tetramers. Immunol Cell Biol. 2018;96(5):507\u201325.","journal-title":"Immunol Cell Biol"},{"key":"7507_CR78","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1146\/annurev-immunol-080719-015428","volume":"38","author":"NM Provine","year":"2020","unstructured":"Provine NM, Klenerman P. MAIT cells in health and disease. Annu Rev Immunol. 2020;38:203\u201328.","journal-title":"Annu Rev Immunol"},{"issue":"2","key":"7507_CR79","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/mi.2014.81","volume":"8","author":"A Kurioka","year":"2015","unstructured":"Kurioka A, Ussher JE, Cosgrove C, et al. MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets. Mucosal Immunol. 2015;8(2):429\u201340.","journal-title":"Mucosal Immunol"},{"key":"7507_CR80","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.3389\/fimmu.2018.01394","volume":"9","author":"D Paquin-Proulx","year":"2018","unstructured":"Paquin-Proulx D, Costa PR, Terrassani Silveira CG, et al. Latent mycobacterium tuberculosis infection is associated with a higher frequency of mucosal-associated invariant T and Invariant natural killer T cells. Front Immunol. 2018;9:1394.","journal-title":"Front Immunol"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-025-07507-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-025-07507-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-025-07507-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T04:56:34Z","timestamp":1768366594000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12967-025-07507-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,10]]},"references-count":80,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["7507"],"URL":"https:\/\/doi.org\/10.1186\/s12967-025-07507-x","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,10]]},"assertion":[{"value":"8 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was conducted according to the principles of the Declaration of Helsinki. Ethics approval was obtained from the LSHTM Research Ethics Committee (#6123; 16\/01\/2012) and the National Research Ethics Service (London: Bloomsbury) Research Ethics Committee REC ref.11\/10\/1760, IRAS ID: 77,765; 22\/12\/2011). Written informed consent was obtained from all study participants prior to inclusion in the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Not Applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"68"}}