{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:27:04Z","timestamp":1783607224560,"version":"3.55.0"},"reference-count":45,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T00:00:00Z","timestamp":1641945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Mucosal-associated invariant T (MAIT) cells are innate like, and play a major role in restricting disease caused by Mycobacterium tuberculosis (Mtb) disease before the activation of antigen-specific T cells. Additionally, the potential link and synergistic function between diabetes mellitus (DM) and tuberculosis (TB) has been recognized for a long time. However, the role of MAIT cells in latent TB (LTB) DM or pre-DM (PDM) and non-DM (NDM) comorbidities is not known. Hence, we examined the frequencies (represented as geometric means, GM) of unstimulated (UNS), mycobacterial (purified protein derivative (PPD) and whole-cell lysate (WCL)), and positive control (phorbol myristate acetate (P)\/ionomycin (I)) antigen stimulated MAIT cells expressing Th1 (IFN\u03b3, TNF\u03b1, and IL-2), Th17 (IL-17A, IL-17F, and IL-22), and cytotoxic (perforin (PFN), granzyme (GZE B), and granulysin (GNLSN)) markers in LTB comorbidities by uniform manifold approximation (UMAP) and flow cytometry. We also performed a correlation analysis of Th1\/Th17 cytokines and cytotoxic markers with HbA1c, TST, and BMI, and diverse hematological and biochemical parameters. The UMAP analysis demonstrated that the percentage of MAIT cells was higher; T helper (Th)1 cytokine and cytotoxic (PFN) markers expressions were different in LTB-DM and PDM individuals in comparison to the LTB-NDM group on UMAP. Similarly, no significant difference was observed in the geometric means (GM) of MAIT cells expressing Th1, Th17, and cytotoxic markers between the study population under UNS conditions. In mycobacterial antigen stimulation, the GM of Th1 (IFN\u03b3 (PPD and WCL), TNF\u03b1 (PPD and WCL), and IL-2 (PPD)), and Th17 (IL-17A, IL-17F, and IL-22 (PPD and\/or WCL)) cytokines were significantly elevated and cytotoxic markers (PFN, GZE B, and GNLSN (PPD and WCL)) were significantly reduced in the LTB-DM and\/or PDM group compared to the LTB-NDM group. Some of the Th1\/Th17 cytokines and cytotoxic markers were significantly correlated with the parameters analyzed. Overall, we found that different Th1 cytokines and cytotoxic marker population clusters and increased Th1 and Th17 (IL-17A, IL-22) cytokines and diminished cytotoxic markers expressing MAIT cells are associated with LTB-PDM and DM comorbidities.<\/jats:p>","DOI":"10.3390\/pathogens11010087","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T04:15:25Z","timestamp":1641960925000},"page":"87","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Multi-Dimensionality Immunophenotyping Analyses of MAIT Cells Expressing Th1\/Th17 Cytokines and Cytotoxic Markers in Latent Tuberculosis Diabetes Comorbidity"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5083-4060","authenticated-orcid":false,"given":"Gokul Raj","family":"Kathamuthu","sequence":"first","affiliation":[{"name":"National Institutes of Health-NIRT-International Center for Excellence in Research, Chennai 600031, India"},{"name":"National Institute for Research in Tuberculosis (NIRT), Chennai 600031, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathella","family":"Pavan Kumar","sequence":"additional","affiliation":[{"name":"National Institutes of Health-NIRT-International Center for Excellence in Research, Chennai 600031, India"},{"name":"National Institute for Research in Tuberculosis (NIRT), Chennai 600031, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kadar","family":"Moideen","sequence":"additional","affiliation":[{"name":"National Institute for Research in Tuberculosis (NIRT), Chennai 600031, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrakumar","family":"Dolla","sequence":"additional","affiliation":[{"name":"National Institute for Research in Tuberculosis (NIRT), Chennai 600031, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Kumaran","sequence":"additional","affiliation":[{"name":"National Institute for Research in Tuberculosis (NIRT), Chennai 600031, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9783-8042","authenticated-orcid":false,"given":"Subash","family":"Babu","sequence":"additional","affiliation":[{"name":"National Institutes of Health-NIRT-International Center for Excellence in Research, Chennai 600031, India"},{"name":"Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1183\/09031936.00120908","article-title":"LTBI: Latent tuberculosis infection or lasting immune responses to M.tuberculosis? A TBNET consensus statement","volume":"33","author":"Mack","year":"2009","journal-title":"Eur. Respir. J."},{"key":"ref_2","unstructured":"World Health Organization (2015). Guidelines on the Management of Latent Tuberculosis Infection, World Health Organization."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s41577-018-0025-3","article-title":"Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection","volume":"18","author":"Simmons","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1056\/NEJMra1405427","article-title":"Latent Mycobacterium tuberculosis infection","volume":"372","author":"Getahun","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1093\/oxfordjournals.aje.a121593","article-title":"The prognosis of a positive tuberculin reaction in childhood and adolescence","volume":"99","author":"Comstock","year":"1974","journal-title":"Am. J. Epidemiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1017\/S0950268897007917","article-title":"The natural history of tuberculosis: The implications of age-dependent risks of disease and the role of reinfection","volume":"119","author":"Vynnycky","year":"1997","journal-title":"Epidemiol. Infect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1093\/aje\/kwt246","article-title":"Estimated rate of reactivation of latent tuberculosis infection in the United States, overall and by population subgroup","volume":"179","author":"Shea","year":"2014","journal-title":"Am. J. Epidemiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/S2213-8587(14)70109-3","article-title":"Improving tuberculosis prevention and care through addressing the global diabetes epidemic: From evidence to policy and practice","volume":"2","author":"Roglic","year":"2014","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kumar, N.P., Banurekha, V.V., Nair, D., Sridhar, R., Kornfeld, H., Nutman, T.B., and Babu, S. (2014). Coincident pre-diabetes is associated with dysregulated cytokine responses in pulmonary tuberculosis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112108"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/nri3813","article-title":"Advancing host-directed therapy for tuberculosis","volume":"15","author":"Wallis","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1146\/annurev-immunol-080719-015428","article-title":"MAIT cells in health and disease","volume":"38","author":"Provine","year":"2020","journal-title":"Annu. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1126\/science.aaw2719","article-title":"Microbial metabolites control the thymic development of mucosal-associated invariant T cells","volume":"366","author":"Legoux","year":"2019","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Viswanathan, V., Kumpatla, S., Aravindalochanan, V., Rajan, R., Chinnasamy, C., Srinivasan, R., Selvam, J.M., and Kapur, A. (2012). Prevalence of diabetes and pre-diabetes and associated risk factors among tuberculosis patients in India. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041367"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3061","DOI":"10.1016\/j.celrep.2019.08.054","article-title":"TCR- or cytokine-activated CD8(+) mucosal- associated invariant T cells are rapid polyfunctional effectors that can coordinate immune responses","volume":"28","author":"Lamichhane","year":"2019","journal-title":"Cell Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3704","DOI":"10.4049\/jimmunol.1401018","article-title":"Microbe-specific unconventional T cells induce human neutrophil differentiation into antigen cross-presenting cells","volume":"193","author":"Davey","year":"2014","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Boulouis, C., Sia, W.R., Gulam, M.Y., Teo, J.Q.M., Png, Y.T., Phan, T.K., Mak, J.Y.W., Fairlie, D.P., Poon, I.K.H., and Koh, T.H. (2020). Human MAIT cell cytolytic effector proteins synergize to overcome carbapenem resistance in Escherichia coli. PLoS Biol., 18.","DOI":"10.1101\/2020.01.16.908806"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2793","DOI":"10.1084\/jem.20160637","article-title":"MAIT cells promote inflammatory monocyte differentiation into dendritic cells during pulmonary intracellular infection","volume":"213","author":"Meierovics","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1111\/imr.12271","article-title":"MR1-restricted mucosal associated invariant T (MAIT) cells in the immune response to Mycobacterium tuberculosis","volume":"264","author":"Gold","year":"2015","journal-title":"Immunol. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/mi.2016.91","article-title":"MR1-restricted mucosal-associated invariant T (MAIT) cells respond to mycobacterial vaccination and infection in nonhuman primates","volume":"10","author":"Greene","year":"2017","journal-title":"Mucosal Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Saeidi, A., Tien Tien, V.L., Al-Batran, R., Al-Darraji, H.A., Tan, H.Y., Yong, Y.K., Ponnampalavanar, S., Barathan, M., Rukumani, D.V., and Ansari, A.W. (2015). Attrition of TCR V\u03b17.2+ CD161++ MAIT cells in HIV-tuberculosis co-infection is associated with elevated levels of PD-1 expression. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124659"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"196","DOI":"10.3109\/15412555.2015.1069806","article-title":"Mucosal-associated invariant T cell deficiency in chronic obstructive pulmonary disease","volume":"13","author":"Kwon","year":"2016","journal-title":"COPD"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Wong, E.B., Akilimali, N.A., Govender, P., Sullivan, Z.A., Cosgrove, C., Pillay, M., Lewinsohn, D.M., Bishai, W.R., Walker, B.D., and Ndung\u2019u, T. (2013). Low levels of peripheral CD161++CD8+ mucosal associated invariant T (MAIT) cells are found in HIV and HIV\/TB co-infection. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0083474"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1164\/rccm.201401-0106OC","article-title":"Mucosal-associated invariant T-cell function is modulated by programmed death-1 signaling in patients with active tuberculosis","volume":"190","author":"Jiang","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.3389\/fimmu.2018.01394","article-title":"Latent Mycobacterium tuberculosis infection is associated with a higher frequency of mucosal-associated invariant t and invariant natural killer T cells","volume":"9","author":"Costa","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Jeon, C.Y., and Murray, M.B. (2008). Diabetes mellitus increases the risk of active tuberculosis: A systematic review of 13 observational studies. PLoS Med., 5.","DOI":"10.1371\/journal.pmed.0050181"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kumar, N.P., Moideen, K., Dolla, C., Kumaran, P., and Babu, S. (2017). Prediabetes is associated with the modulation of antigen-specific Th1\/Tc1 and Th17\/Tc17 responses in latent Mycobacterium tuberculosis infection. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178000"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1002\/eji.201545973","article-title":"Coincident diabetes mellitus modulates Th1-, Th2-, and Th17-cell responses in latent tuberculosis in an IL-10- and TGF-beta-dependent manner","volume":"46","author":"Kumar","year":"2016","journal-title":"Eur. J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1093\/infdis\/jiv484","article-title":"Impaired cytokine but enhanced cytotoxic marker expression in Mycobacterium tuberculosis-induced CD8+ T cells in individuals with Type 2 Diabetes and latent Mycobacterium tuberculosis infection","volume":"213","author":"Kumar","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1093\/infdis\/jiu329","article-title":"Diminished systemic and antigen-specific type 1, type 17, and other proinflammatory cytokines in diabetic and prediabetic individuals with latent Mycobacterium tuberculosis infection","volume":"210","author":"Kumar","year":"2014","journal-title":"J. Infect Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"71","DOI":"10.5588\/ijtld.15.0457","article-title":"Increased risk of latent tuberculous infection among persons with pre-diabetes and diabetes mellitus","volume":"20","author":"Hensel","year":"2016","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Almeida-Junior, J.L., Gil-Santana, L., Oliveira, C.A., Castro, S., Cafezeiro, A.S., Daltro, C., Netto, E.M., Kornfeld, H., and Andrade, B.B. (2016). Glucose metabolism disorder is associated with pulmonary tuberculosis in individuals with respiratory symptoms from Brazil. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0153590"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1146\/annurev-immunol-032712-095939","article-title":"The immune response in tuberculosis","volume":"31","author":"Garra","year":"2013","journal-title":"Annu. Rev. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1146\/annurev.immunol.021908.132703","article-title":"Cell-mediated immune responses in tuberculosis","volume":"27","author":"Cooper","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.4049\/jimmunol.1101122","article-title":"Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load","volume":"187","author":"Day","year":"2011","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/nm.2299","article-title":"Dominant TNF-alpha+ Mycobacterium tuberculosis-specific CD4+ T cell responses discriminate between latent infection and active disease","volume":"17","author":"Harari","year":"2011","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.3389\/fimmu.2017.01252","article-title":"IL-17 Production from T Helper 17, Mucosal-associated invariant T and \u03b3\u03b4 cells in tuberculosis infection and disease","volume":"8","author":"Coulter","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1111\/imcb.12021","article-title":"Human blood MAIT cell subsets defined using MR1 tetramers","volume":"96","author":"Gherardin","year":"2018","journal-title":"Immunol. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Gold, M.C., Cerri, S., Smyk-Pearson, S., Cansler, M.E., Vogt, T.M., Delepine, J., Winata, E., Swarbrick, G.M., Chua, W.J., and Yu, Y.Y. (2010). Human mucosal associated invariant T cells detect bacterially infected cells. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000407"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"32320","DOI":"10.1038\/srep32320","article-title":"Enhanced immune response of MAIT cells in tuberculous pleural effusions depends on cytokine signaling","volume":"6","author":"Jiang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Gopal, R., Monin, L., Slight, S., Uche, U., Blanchard, E., Fallert Junecko, B.A., Ramos-Payan, R., Stallings, C.L., Reinhart, T.A., and Kolls, J.K. (2014). Unexpected role for IL-17 in protective immunity against hypervirulent Mycobacterium tuberculosis HN878 infection. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004099"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Hur, Y.G., Gorak-Stolinska, P., Ben-Smith, A., Lalor, M.K., Chaguluka, S., Dacombe, R., Doherty, T.M., Ottenhoff, T.H., Dockrell, H.M., and Crampin, A.C. (2013). Combination of cytokine responses indicative of latent TB and active TB in Malawian adults. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079742"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3142","DOI":"10.4049\/jimmunol.1203218","article-title":"IL-7 licenses activation of human liver intrasinusoidal mucosal-associated invariant T cells","volume":"190","author":"Tang","year":"2013","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"756854","DOI":"10.3389\/fcimb.2021.756854","article-title":"Decreased frequencies of gamma\/delta T cells expressing Th1\/Th17 cytokine, cytotoxic, and immune markers in latent tuberculosis-diabetes\/pre-diabetes comorbidity","volume":"11","author":"Kathamuthu","year":"2021","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.3389\/fimmu.2017.01837","article-title":"Mucosal-associated invariant T cell interactions with commensal and pathogenic bacteria: Potential role in antimicrobial immunity in the child","volume":"8","author":"Ghazarian","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.tim.2020.11.008","article-title":"Emerging role for MAIT cells in control of antimicrobial resistance","volume":"29","author":"Leeansyah","year":"2021","journal-title":"Trends Microbiol."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/11\/1\/87\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:02:05Z","timestamp":1760364125000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/11\/1\/87"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,12]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["pathogens11010087"],"URL":"https:\/\/doi.org\/10.3390\/pathogens11010087","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,12]]}}}