{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T12:33:52Z","timestamp":1793709232878,"version":"4.6.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"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>\n                    Immunity in tuberculosis (TB) infection is complex as\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (MTB) is a highly adaptive pathogen and may escape the immune defense through various ways. During MTB infection, immune modulation involves the activation and regulation of various immune cells and signaling pathways to mount an effective defense against the pathogen while minimizing immune pathology. Host pathogen interactions in TB are complex as MTB is a pathogen that is able to adapt and survive and may escape the immune defense through various ways. The limitations of BCG vaccine have energized researchers to identify alternative vaccines for TB. For the rational design of new efficacious and safe vaccines against TB, advanced knowledge of protective and pathological immune responses in TB is needed. It has been well established that the existing anti-TB treatment (ATT) induced an enhanced production of IL-2 and IFN-\u03b3 by T cells. This study explores modulations in the activation\/phosphorylation of T-cell signaling molecules in the peripheral blood of TBP patients following 6 months of treatment. We reviewed existing evidence on TCR signaling alterations in TB and propose mechanisms by which treatment influences the activation of intracellular calcium mobilization and ZAP-70, PKC-theta, and MAPK activation, which is finally impacting T-cell function by regulating the production of cytokines and impacting the immune control of MTB. Our findings suggest that while treatment reduces bacterial burden, residual immune dysregulation in T-cell activation pathways may persist, influencing long-term T-cell responses. Further studies are needed to fully elucidate these changes and their implications for relapse prevention and therapeutic strategies.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2025.1645200","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T06:24:04Z","timestamp":1764570244000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Impact of anti-TB drugs on modulations of T-cell-receptor-mediated signaling events in TB pleurisy patients"],"prefix":"10.3389","volume":"16","author":[{"given":"Bhawna","family":"Sharma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beenu","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santosh","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"key":"B1","volume-title":"Global tuberculosis report","year":"2024"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2018.00158","article-title":"Mycobacterium tuberculosis: an adaptable pathogen associated with multiple human diseases","volume":"8","author":"Chai","year":"2018","journal-title":"Front Cell Infect Microbiol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"57","DOI":"10.3390\/vaccines10010057","article-title":"After 100 years of BCG immunization against tuberculosis, what is new and still outstanding for this vaccine","volume":"10","author":"Flores-Valdez","year":"2021","journal-title":"Vaccines (Basel)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13191","article-title":"Is mapping the BCG vaccine-induced immune responses the key to improving the efficacy against tuberculosis","volume":"288","author":"Kuan","year":"2020","journal-title":"J Intern Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-020-00794-0","article-title":"Towards new TB vaccines","volume":"42","author":"Brazier","year":"2020","journal-title":"Semin Immunopathol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2016.5364","article-title":"Ag85A\/ESAT-6 chimeric DNA vaccine induces an adverse response in tuberculosis-infected mice","volume":"14","author":"Liang","year":"2016","journal-title":"Mol Med Rep"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e0041224","DOI":"10.1128\/spectrum.00412-24","article-title":"Immunoinhibitory effects of anti-tuberculosis therapy induce the host vulnerability to tuberculosis recurrence","volume":"12","author":"Pahuja","year":"2024","journal-title":"Microbiol Spectr"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C114.598946","article-title":"Isoniazid induces apoptosis of activated CD4+ T cells","volume":"289","author":"Tousif","year":"2014","journal-title":"J Biol Chem"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.4103\/ijmy.ijmy_172_20","article-title":"Investigating role of Mycobacterium tuberculosis secretory antigens in altering activation of T cell signaling events in Jurkat T cells","volume":"9","author":"Sharma","year":"2020","journal-title":"Int J Mycobacteriol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2025.102615","article-title":"Unraveling the role of the immune landscape in tuberculosis granuloma","volume":"152","author":"Jaiswal","year":"2025","journal-title":"Tuberculosis (Edinb)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2017.113","article-title":"Th1 cytokines, true functional signatures for protective immunity against TB","volume":"15","author":"Zeng","year":"2018","journal-title":"Cell Mol Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s43042-022-00358","article-title":"Mendelian susceptibility to mycobacterial disease: an overview","volume":"24","author":"Errami","year":"2023","journal-title":"Egypt J Med Hum Genet"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2015.08.003","article-title":"Immune parameters differentiating active from latent tuberculosis infection in humans","volume":"95","author":"Lee","year":"2015","journal-title":"Tuberculosis (Edinb)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.5588\/ijtld.16.0880","article-title":"Interferon-gamma response to the treatment of active pulmonary and extra-pulmonary tuberculosis","volume":"21","author":"Liang","year":"2017","journal-title":"Int J Tuberc Lung Dis"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/genes4020101","article-title":"The role of mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) in inflammation","volume":"4","author":"Moens","year":"2013","journal-title":"Genes (Basel)"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jis672","article-title":"Phosphorylation of mitogen-activated protein kinases contributes to interferon \u03b3 production in response to mycobacterium tuberculosis","volume":"207","author":"Pasquinelli","year":"2013","journal-title":"J Infect Dis"},{"key":"B17","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1128\/MMBR.00031-10","article-title":"Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases","volume":"75","author":"Cargnello","year":"2011","journal-title":"Microbiol Mol Biol Rev"},{"key":"B18","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/s41392-021-00823-w","article-title":"T cell receptor (TCR) signaling in health and disease","volume":"6","author":"Shah","year":"2021","journal-title":"Sig Transduct Target Ther"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2567.2001.01323.x","article-title":"and Maeurer MJ: Reduced T-cell receptor CD3\u03be-chain protein and sustained CD3\u03f5 expression at the site of mycobacterial infections","volume":"104","author":"Seitzer","year":"2001","journal-title":"Immunology"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803579","article-title":"ESAT-6 inhibits production of IFN-gamma by Mycobacterium tuberculosis-responsive human T cells","volume":"182","author":"Wang","year":"2009","journal-title":"J Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00222-09","article-title":"Mycobacterium tuberculosis cell wall glycolipids directly inhibit CD4+ T cell activation by interfering with proximal T-cell receptor signalling","volume":"10","author":"Mahon","year":"2009","journal-title":"Infect Immun"},{"key":"B22","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.cellimm.2012.02.009","article-title":"Mycobacterium tuberculosis ManLAM inhibits T-cell-receptor signalling by interference with ZAP-70, Lck and LAT phosphorylation","volume":"275","author":"Mahon","year":"2012","journal-title":"Cell Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2009.03.010","article-title":"Mycobacterial di-O-acyl trehalose inhibits Th-1cytokine gene expression in murine cells by down-modulation of MAPK signalling","volume":"215","author":"Palma-Nicol\u00e1s","year":"2010","journal-title":"Immunobiology"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.234062","article-title":"The Mycobacterium tuberculosis early secreted antigenic target of 6 kDa inhibits T cell interferon-\u03b3 production through the p38 mitogen-activated protein kinase pathway","volume":"286","author":"Peng","year":"2011","journal-title":"J Biol Chem"},{"key":"B25","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/s12865-015-0128-6","article-title":"Mycobacterium tuberculosis secretory proteins downregulate T cell activation by interfering with proximal and downstream T cell signalling events","volume":"16","author":"Sharma","year":"2015","journal-title":"BMC Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.780453","article-title":"T helper cell subsets in the pleural fluid of tuberculous patients differentiate patients with nonTuberculous pleural effusions","volume":"12","author":"Roofchayee","year":"2021","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00381-07","article-title":"Mycobacterium tuberculosis-Induced gamma interferon production by natural killer cells Requires cross talk with antigen-presenting cells involving Toll-Like Receptors 2 and 4 and the Mannose Receptor in Tuberculous Pleurisy","volume":"11","author":"Schierloh","year":"2007","journal-title":"Infect Immun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.983605","article-title":"Exploring modulations in T-cell receptor-mediated T-cell signaling events in systemic circulation and at local disease site of patients with tubercular pleural effusion: An attempt to understand tuberculosis pathogenesis at the local disease site","volume":"9","author":"Sharma","year":"2022","journal-title":"Front Med (Lausanne)"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)83641-4","article-title":"A new generation of Ca2+ indicators with greatly improved fluorescence properties","volume":"260","author":"Grynkiewicz","year":"1985","journal-title":"J Biol Chem"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-006-9132-8","article-title":"On cell signalling mechanism of Mycobaterium leprae soluble antigen (MLSA) in Jurkat T-cells","volume":"287","author":"Joshi","year":"2006","journal-title":"Mol Cell Biochem"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00180","article-title":"Functional signatures of human CD4 and CD8 T cell responses to mycobacterium tuberculosis","volume":"5","author":"Prezzemolo","year":"2014","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e1010721","DOI":"10.1371\/journal.ppat.1010721","article-title":"IFN-\u03b3-independent control of M. tuberculosis requires CD4 T cell-derived GM-CSF and activation of HIF-1\u03b1","volume":"18","author":"Van Dis","year":"2022","journal-title":"PloS Pathog"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02350","article-title":"IL-2 restores T-cell dysfunction induced by persistent mycobacterium tuberculosis antigen stimulation.","volume":"10","author":"Liu","year":"2019","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/s40169-017-0151-8","article-title":"IFN\u03b3-producing CD4+ T lymphocytes: the double-edged swords in tuberculosis","volume":"6","author":"Kumar","year":"2017","journal-title":"Clin Transl Med"},{"key":"B35","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s40635-019-0287-5","article-title":"Intracellular calcium signaling and phospho-antigen measurements reveal functional proximal TCR activation in lymphocytes from septic shock patients","volume":"7","author":"de Roquetaillade","year":"2019","journal-title":"ICMx"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.1998.00489.x","article-title":"Phenotypic changes in T cell populations during the reactivation of tuberculosis in mice","volume":"111","author":"Howard","year":"1998","journal-title":"Clin Exp Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.2174\/1871530311006040367","article-title":"PKC-\u03b8 is a drug target for prevention of T cell-mediated autoimmunity and allograft rejection","volume":"10","author":"Kwon","year":"2010","journal-title":"Endocr Metab Immune Disord Drug Targets"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00321","article-title":"The immunodominant T-cell epitopes of the mycolyl-transferases of the antigen 85 complex of M","volume":"5","author":"Huygen","year":"2014","journal-title":"tuberculosis. Front Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1383098","article-title":"The role of ESAT-6 in tuberculosis immunopathology","volume":"15","author":"Passos","year":"2024","journal-title":"Front Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/j.tube.2015.07.002","article-title":"Interferon gamma release assays for monitoring the response to treatment for tuberculosis: A systematic review","volume":"95","author":"Clifford","year":"2015","journal-title":"Tuberculosis (Edinb)"},{"key":"B41","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s12865-019-0317-9","article-title":"Enhanced IFN-\u03b3, but not IL-2, response to Mycobacterium tuberculosis antigens in HIV\/latent TB co-infected patients on long-term HAART","volume":"20","author":"Desalegn","year":"2019","journal-title":"BMC Immunol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"17854","DOI":"10.1038\/s41598-017-18200-5","article-title":"Clinical and\u00a0immunological effects of rhIL-2 therapy in eastern chinese patients with multidrug-resistant tuberculosis","volume":"7","author":"Tan","year":"2017","journal-title":"Sci Rep"},{"key":"B43","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.tube.2017.07.013","article-title":"Multiplex analysis of plasma cytokines\/chemokines showing different immune responses in active TB patients, latent TB infection and healthy participants","volume":"107","author":"Yao","year":"2017","journal-title":"Tuberculosis (Edinb)"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4103\/ijmy.ijmy_164_17","article-title":"Patients at high risk of tuberculosis recurrence","volume":"7","author":"Mirsaeidi","year":"2018","journal-title":"Int J Mycobacteriol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"ofz257","DOI":"10.1093\/ofid\/ofz257","article-title":"Plasma proinflammatory cytokines are markers of disease severity and bacterial burden in pulmonary tuberculosis","volume":"6","author":"Nathella","year":"2019","journal-title":"Open Forum Infect Dis"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms9122460","article-title":"T-cell exhaustion in mycobacterium tuberculosis and nontuberculous mycobacteria infection: pathophysiology and therapeutic perspectives","volume":"9","author":"Lombardi","year":"2021","journal-title":"Microorganisms"},{"key":"B48","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1128\/CVI.05263-11","article-title":"Increased frequency of regulatory T cells and T lymphocyte activation in persons with previously treated extrapulmonary tuberculosis","volume":"19","author":"de Almeida","year":"2012","journal-title":"Clin Vaccine Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1545537","article-title":"Increased long-term central memory T cells in patients with retreatment pulmonary tuberculosis","volume":"16","author":"Yao","year":"2025","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1645200\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T06:24:04Z","timestamp":1764570244000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1645200\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,1]]},"references-count":49,"alternative-id":["10.3389\/fimmu.2025.1645200"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1645200","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,1]]},"article-number":"1645200"}}