{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T16:36:16Z","timestamp":1794242176906,"version":"4.9.0"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>This study aimed to investigate the causal or casual relation between dysregulated glucose metabolism and meta-inflammation in type 2 diabetes mellitus (T2DM), and more importantly the mediators and cellular sources for this meta-inflammation. We examined whether T2DM meta-inflammation is driven by aberrant, inflamed T-helper cells and if there was a direct link to HbA1c levels. Flow cytometry data revealed TNF-\u03b1\u2212secreting effector CD4<jats:sup>+<\/jats:sup> T cells as key contributors to inflammation, while memory T cells secreting GM-CSF and IL-17 escalated and maintained meta-inflammation. Crucially, these cytokines were present even in the \u201cresting CD4<jats:sup>+<\/jats:sup> T cells,\u201d reflecting an aberrant, low-grade, chronically activated, and inflamed immune system. Significantly, higher antibody isotype levels further substantiated these findings as proof of concept for sustained and inflamed APC-T cell-B cell nexus. while reduced IL-10 levels reflected a shift towards pro-inflammatory bias. Functional assays, phospho-protein expression, <jats:italic>ex-vivo<\/jats:italic> inhibitor studies, and confocal microscopy confirmed that basal meta-inflammation in T2DM is exclusively mediated by multiple T-helper cell phenotypes via the TNF-\u03b1\/STAT-3-signaling axis. Plasma cytokine and antibody isotyping were profiled using multiplex immunoassays from undiluted plasma. Taken together, these findings suggest that unchecked cytokine secretion, inflamed T-helper subsets, unwarranted antibody isotypes, and so forth, may contribute to organ damage by further amplifying innate and adaptive immune responses. Monitoring inflammatory cytokines, antibody isotypes, and T-helper cell subsets could significantly mitigate organ damage in T2DM, offering a more comprehensive approach to disease management. Thus, this study highlights the importance of not only achieving metabolic control during T2DM treatment but also monitoring and regulating immune homeostasis.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1603484","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T04:13:19Z","timestamp":1757909599000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Meta-inflammation in type 2 diabetes mellitus: unveiling the role of aberrant CD4+ T cells and pro-inflammatory cytokine networks"],"prefix":"10.3389","volume":"16","author":[{"given":"Shubham K.","family":"Shaw","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumya","family":"Sengupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohila","family":"Jha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrasekhar","family":"Pattanaik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harapriya","family":"Behera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakash K.","family":"Barik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dayanidhi","family":"Meher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajlaxmi","family":"Sarangi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish","family":"Devadas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21176275","article-title":"Pathophysiology of type 2 diabetes mellitus","volume":"21","author":"Galicia-Garcia","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B2","doi-asserted-by":"publisher","first-page":"6264149","DOI":"10.1155\/2016\/6264149","article-title":"Metainflammation in diabetic coronary artery disease: emerging role of innate and adaptive immune responses","volume":"2016","author":"Aravindhan","year":"2016","journal-title":"J Diabetes Res"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24108643","article-title":"Meta-inflammation and new anti-diabetic drugs: A new chance to knock down residual cardiovascular risk","volume":"24","author":"d'Aiello","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B4","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s12902-021-00925-0","article-title":"Clinical and biological risk factors associated with inflammation in patients with type 2 diabetes mellitus","volume":"22","author":"Ellulu","year":"2022","journal-title":"BMC Endocr Disord"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e516","DOI":"10.1002\/mco2.516","article-title":"Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions","volume":"5","author":"Zhao","year":"2024","journal-title":"MedComm (2020)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-4454","article-title":"Association between inflammation and biological variation in hemoglobin A1c in U.S. Nondiabetic adults","volume":"100","author":"Liu","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.4068\/cmj.2021.57.1.62","article-title":"Relationship between hs-CRP and hbA1c in diabetes mellitus patients: 2015\u20132017 Korean national health and nutrition examination survey","volume":"57","author":"Seo","year":"2021","journal-title":"Chonnam Med J"},{"key":"B8","doi-asserted-by":"publisher","first-page":"110069","DOI":"10.1016\/j.diabres.2022.110069","article-title":"Mean HbA1c and HbA1c variability are associated with differing diabetes-related complications in patients with type 2 diabetes mellitus","volume":"192","author":"Wu","year":"2022","journal-title":"Diabetes Res Clin Pract"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01582","article-title":"The effects of type 2 diabetes mellitus on organ metabolism and the immune system","volume":"11","author":"Daryabor","year":"2020","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"108637","DOI":"10.1016\/j.diabres.2020.108637","article-title":"Type 2 diabetes and viral infection; cause and effect of disease","volume":"172","author":"Turk Wensveen","year":"2021","journal-title":"Diabetes Res Clin Pract"},{"key":"B11","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s10020-024-00824-9","article-title":"An update on chronic complications of diabetes mellitus: from molecular mechanisms to therapeutic strategies with a focus on metabolic memory","volume":"30","author":"Yang","year":"2024","journal-title":"Mol Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8122219","article-title":"Type 2 diabetes mellitus and altered immune system leading to susceptibility to pathogens, especially mycobacterium tuberculosis","volume":"8","author":"Ferlita","year":"2019","journal-title":"J Clin Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/s11892-017-0900-5","article-title":"T cell populations and functions are altered in human obesity and type 2 diabetes","volume":"17","author":"Touch","year":"2017","journal-title":"Curr Diabetes Rep"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.848335","article-title":"Underlying co-morbidity reveals unique immune signatures in type II diabetes patients infected with SARS-coV2","volume":"13","author":"Sengupta","year":"2022","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1172\/JCI88876","article-title":"Role of innate and adaptive immunity in obesity-associated metabolic disease","volume":"127","author":"McLaughlin","year":"2017","journal-title":"J Clin Invest"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M800019-JLR200","article-title":"Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice","volume":"49","author":"Murano","year":"2008","journal-title":"J Lipid Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1080\/21623945.2021.1965314","article-title":"The roles of T cells in obese adipose tissue inflammation","volume":"10","author":"Wang","year":"2021","journal-title":"Adipocyte"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02509","article-title":"T cells in adipose tissue: critical players in immunometabolism","volume":"9","author":"Wang","year":"2018","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2018.01.018","article-title":"Biology and function of adipose tissue macrophages, dendritic cells and B cells","volume":"271","author":"Ivanov","year":"2018","journal-title":"Atherosclerosis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2024.1396161","article-title":"Association between neutrophil-to-lymphocyte ratio and diabetic retinopathy in patients with type 2 diabetes: a cohort study","volume":"15","author":"Tang","year":"2024","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1393392","article-title":"The role and therapeutic potential of macrophages in the pathogenesis of diabetic cardiomyopathy","volume":"15","author":"Zhang","year":"2024","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fragi.2024.1490302","article-title":"The 3 I\u2019s of immunity and aging: immunosenescence, inflammaging, and immune resilience","volume":"5","author":"Wrona","year":"2024","journal-title":"Front Aging"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1537909","article-title":"Immunometabolic alterations in type 2 diabetes mellitus revealed by single-cell RNA sequencing: insights into subtypes and therapeutic targets","volume":"15","author":"Li","year":"2024","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"6494795","DOI":"10.1155\/2017\/6494795","article-title":"Role of T lymphocytes in type 2 diabetes and diabetes-associated inflammation","volume":"2017","author":"Xia","year":"2017","journal-title":"J Diabetes Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.26502\/aimr.0178","article-title":"NLRP3 inflammasome and gut dysbiosis linking diabetes mellitus and inflammatory bowel disease","volume":"7","author":"Malicevic","year":"2024","journal-title":"Arch Intern Med Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2011.09.029","article-title":"Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: a cross-sectional study","volume":"57","author":"Mirza","year":"2012","journal-title":"Cytokine"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.01607","article-title":"Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes","volume":"10","author":"Zatterale","year":"2019","journal-title":"Front Physiol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01041","article-title":"Inducible costimulator expressing T cells promote parasitic growth during blood stage plasmodium berghei ANKA infection","volume":"9","author":"Jogdand","year":"2018","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005777","article-title":"Pathological manifestations in lymphatic filariasis correlate with lack of inhibitory properties of IgG4 antibodies on IgE-activated granulocytes","volume":"11","author":"Prodjinotho","year":"2017","journal-title":"PloS Negl Trop Dis"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.crimmu.2021.10.002","article-title":"Optimization of stimulation and staining conditions for intracellular cytokine staining (ICS) for determination of cytokine-producing T cells and monocytes","volume":"2","author":"Mandala","year":"2021","journal-title":"Curr Res Immunol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"6 24 1","DOI":"10.1002\/0471142735.im0624s110","article-title":"Detection of intracellular cytokines by flow cytometry","volume":"110","author":"Yin","year":"2015","journal-title":"Curr Protoc Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1002\/cyto.a.10072","article-title":"Intracellular phospho-protein staining techniques for flow cytometry: monitoring single cell signaling events","volume":"55","author":"Krutzik","year":"2003","journal-title":"Cytometry A"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00083","article-title":"iCa(2+) flux, ROS and IL-10 determines cytotoxic, and suppressor T cell functions in chronic human viral infections","volume":"11","author":"Mohanty","year":"2020","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12010181","article-title":"IL-21, inflammatory cytokines and hyperpolarized CD8(+) T cells are central players in lupus immune pathology","volume":"12","author":"Sengupta","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1235514","article-title":"IL-21\/23 axis modulates inflammatory cytokines and RANKL expression in RA CD4(+) T cells via p-Akt1 signaling","volume":"14","author":"Bhattacharya","year":"2023","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3987","DOI":"10.1038\/ncomms4987","article-title":"Combinatorial flexibility of cytokine function during human T helper cell differentiation","volume":"5","author":"Touzot","year":"2014","journal-title":"Nat Commun"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1423766","article-title":"Antigen-specific T helper cells and cytokine profiles predict intensity and longevity of cellular and humoral responses to SARS-CoV-2 booster vaccination","volume":"15","author":"Page","year":"2024","journal-title":"Front Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1394108","article-title":"Macrophage polarization in rheumatoid arthritis: signaling pathways, metabolic reprogramming, and crosstalk with synovial fibroblasts","volume":"15","author":"Zheng","year":"2024","journal-title":"Front Immunol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"503437","DOI":"10.1016\/j.mrgentox.2021.503437","article-title":"Mechanisms underlying the pathophysiology of type 2 diabetes: From risk factors to oxidative stress, metabolic dysfunction, and hyperglycemia","author":"Lima","year":"2022","journal-title":"Mutat Res Genet Toxicol Environ Mutagen"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2022.12.004","article-title":"Inflammatory and immune etiology of type 2 diabetes","volume":"44","author":"Bl\u00e9riot","year":"2023","journal-title":"Trends Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.molimm.2024.03.009","article-title":"IL-17 in type II diabetes mellitus (T2DM) immunopathogenesis and complications; molecular approaches","volume":"171","author":"Elahi","year":"2024","journal-title":"Mol Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26041730","article-title":"Characterization of anti-insulin antibodies in type 1 and type 2 diabetes mellitus: clinical relevance","volume":"26","author":"Toft-Hansen","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B43","doi-asserted-by":"publisher","first-page":"29","DOI":"10.5114\/ceji.2020.94670","article-title":"Th17 and regulatory T cells in patients with different time of progression of type 2 diabetes mellitus","volume":"45","author":"Guzm\u00e1n-Flores","year":"2020","journal-title":"Cent Eur J Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13187","article-title":"Functional status of immune cells in patients with long-lasting type 2 diabetes mellitus","volume":"194","author":"Nam","year":"2018","journal-title":"Clin Exp Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3390\/nu16101404","article-title":"Fasting and glucose metabolism differentially impact peripheral inflammation in human type 2 diabetes","volume":"16","author":"Kalantar","year":"2024","journal-title":"Nutrients"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.2337\/db21-0659","article-title":"Regulatory T cells control effector T cell inflammation in human prediabetes","volume":"71","author":"Liu","year":"2022","journal-title":"Diabetes"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1186\/s41983-019-0080-0","article-title":"Tumor necrosis factor alpha in peripheral neuropathy in type 2 diabetes mellitus","volume":"55","author":"El Sheikh","year":"2019","journal-title":"Egyptian J Neurol Psychiatry Neurosurg"},{"key":"B48","doi-asserted-by":"publisher","first-page":"100940","DOI":"10.1016\/j.preteyeres.2021.100940","article-title":"The innate immune system in diabetic retinopathy","volume":"84","author":"Pan","year":"2021","journal-title":"Prog Retin Eye Res"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e49926","DOI":"10.7759\/cureus.49926","article-title":"Unraveling the role of tumor necrosis factor-alpha in diabetic peripheral neuropathy: A systematic review and meta-analysis","volume":"15","author":"Sen","year":"2023","journal-title":"Cureus"},{"key":"B50","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1038\/s41392-024-01951-9","article-title":"Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy","volume":"9","author":"Lu","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.15420\/ecr","article-title":"The role of inflammation in diabetes: current concepts and future perspectives","volume":"14","author":"Tsalamandris","year":"2019","journal-title":"Eur Cardiol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1038\/nri2925","article-title":"Type 2 diabetes as an inflammatory disease","volume":"11","author":"Donath","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2353","article-title":"B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies","volume":"17","author":"Winer","year":"2011","journal-title":"Nat Med"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.17489","article-title":"STAT3 regulates inflammatory cytokine production downstream of TNFR1 by inducing expression of TNFAIP3\/A20","volume":"26","author":"Antonia","year":"2022","journal-title":"J Cell Mol Med"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00784","article-title":"Role of TNF-TNF receptor 2 signal in regulatory T cells and its therapeutic implications","volume":"9","author":"Yang","year":"2018","journal-title":"Front Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1093\/ibd\/izac199","article-title":"The pathogenicity and synergistic action of th1 and th17 cells in inflammatory bowel diseases","volume":"29","author":"Cao","year":"2023","journal-title":"Inflammation Bowel Dis"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1177\/0091270007301623","article-title":"The role of TNFalpha in ulcerative colitis","volume":"47","author":"Sands","year":"2007","journal-title":"J Clin Pharmacol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.3.1181","article-title":"1,25-dihydroxyvitamin D3 inhibits IFN-\u03b3 and IL-4 levels during in vitro polarization of primary murine CD4+ T cells","volume":"168","author":"Staeva-Vieira","year":"2002","journal-title":"J Immunol"},{"key":"B59","doi-asserted-by":"publisher","first-page":"181643","DOI":"10.1155\/2015\/181643","article-title":"Molecular events linking oxidative stress and inflammation to insulin resistance and beta-cell dysfunction","volume":"2015","author":"Keane","year":"2015","journal-title":"Oxid Med Cell Longev"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.4110\/in.2022.22.e13","article-title":"The role of T cells in obesity-associated inflammation and metabolic disease","volume":"22","author":"Park","year":"2022","journal-title":"Immune Netw"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.arcmed.2020.11.012","article-title":"Increasing imbalance of treg\/th17 indicates more severe glucose metabolism dysfunction in overweight\/obese patients","volume":"52","author":"Wen","year":"2021","journal-title":"Arch Med Res"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22052719","article-title":"The role of tumor necrosis factor alpha (TNF-alpha) in autoimmune disease and current TNF-alpha inhibitors in therapeutics","volume":"22","author":"Jang","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-11-4567","article-title":"TNF downmodulates the function of human CD4+CD25hi T-regulatory cells","volume":"108","author":"Valencia","year":"2006","journal-title":"Blood"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1603484\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T04:13:23Z","timestamp":1757909603000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1603484\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,15]]},"references-count":63,"alternative-id":["10.3389\/fimmu.2025.1603484"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1603484","relation":{"has-part":[{"id-type":"doi","id":"https:\/\/doi.org\/10.3389\/fimmu.2025.1603484.s001","asserted-by":"subject"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,15]]},"article-number":"1603484"}}