{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T03:14:30Z","timestamp":1771470870809,"version":"3.50.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T00:00:00Z","timestamp":1741219200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Tuberc."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Interferon-gamma release assays (IGRAs), such as the T-SPOT.<jats:italic>TB<\/jats:italic> and QuantiFERON-TB Gold, are commonly used to detect immune responses to Mycobacterium tuberculosis (M.tb) and identify latent TB infection. However, their role in reflecting immune dynamics within tissues, especially in the absence of active disease, remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Post-mortem tissues, including lung, lymph nodes, spleen, and bronchoalveolar lavage, were collected from apparently healthy, HIV-negative road traffic accident victims. M.tb infection was ruled out using liquid MGIT culture, while M.tb exposure history was assessed with the TSPOT.<jats:italic>TB<\/jats:italic> assay. T and B cell phenotyping was performed using a 29-color flow cytometry panel, with data analyzed in FlowJo and GraphPad Prism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of the 52 individuals recruited, 48% were IGRA-positive (TSPOT+). Using a 29-color flow cytometry panel, we analyzed T and B cell populations across various tissues. We observed similar overall frequencies of CD3, CD4, CD8, and CD19 cells, as well as memory T and B cell subsets defined by CCR7\/CD45RA and IgD\/CD27 between TSPOT+ and TSPOT individuals. Notably, in the lungs, TSPOT+ individuals exhibited a higher frequency of CD4+ tissue-resident memory (TRM) T cells, along with increased expression of KLRG1, a marker of terminal differentiation, on mature CD4+CD27 T cells. This phenotype was specific to CD4 T cells in the lungs, highlighting the known role of CD4 T cells in TB immunity and their localization to the primary site of infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our findings suggest that IGRA positivity, while indicating immune memory, may also be associated with highly differentiated CD4 T cells in tissue-specific compartments, particularly in the lungs. These localized immune changes raise important questions about the long-term effects of chronic immune engagement following repeated M.tb exposure in endemic settings. Further research is needed to assess the clinical implications of these findings, including their impact on susceptibility to future infections or disease progression.<\/jats:p><\/jats:sec>","DOI":"10.3389\/ftubr.2025.1535945","type":"journal-article","created":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T06:52:39Z","timestamp":1741243959000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Tissue-specific T cell profiles in Mycobacterium tuberculosis uninfected IGRA negative and positive individuals"],"prefix":"10.3389","volume":"3","author":[{"given":"Gift","family":"Ahimbisibwe","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjorie","family":"Nakibuule","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marvin Martin","family":"Ssejjoba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire Precious","family":"Bisoboka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feddy Gift","family":"Akello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marvin Joven","family":"Turyasingura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rose","family":"Mulwana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josephine","family":"Nabulime","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Febronius","family":"Babirye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Musana Abdusalaamu","family":"Kizito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Herv\u00e9 Monka","family":"Lekuya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akello Suzan","family":"Adakun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisy","family":"Nalumansi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stella","family":"Muryasingura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Lukande","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph Baruch","family":"Baluku","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene Andia","family":"Biraro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Cose","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3229","DOI":"10.1128\/JCM.37.10.3229-3232.1999","article-title":"Evaluation of the tuberculin gamma interferon assay: potential to replace the mantoux skin test","volume":"37","author":"Pottumarthy","year":"1999","journal-title":"J Clin Microbiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1093\/clinids\/17.6.968","article-title":"The tuberculin skin test","volume":"17","author":"Huebner","year":"1993","journal-title":"Clin Infect Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1128\/CDLI.6.6.934-937.1999","article-title":"Tuberculin-purified protein derivative-, MPT-64-, and ESAT-6-stimulated gamma interferon responses in medical students before and after Mycobacterium bovis BCG vaccination and in patients with tuberculosis","volume":"6","author":"Johnson","year":"1999","journal-title":"Clin Diagn Lab Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ijid.2015.01.017","article-title":"Frequency of Mycobacterium tuberculosis-specific CD8+ T-cells in the course of anti-tuberculosis treatment","volume":"32","author":"Axelsson-Robertson","year":"2015","journal-title":"Int J Infect Dis."},{"key":"B5","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1128\/CDLI.5.4.531-536.1998","article-title":"Development of a human gamma interferon enzyme immunoassay and comparison with tuberculin skin testing for detection of Mycobacterium tuberculosis infection","volume":"5","author":"Desem","year":"1998","journal-title":"Clin Diagn Lab Immunol."},{"key":"B6","first-page":"725","article-title":"Basic characteristics of a novel diagnostic method (QuantiFERON TB-2G) for latent tuberculosis infection with the use of Mycobacterium tuberculosis-specific antigens, ESAT-6 and CFP-10","volume":"79","author":"Harada","year":"2004","journal-title":"Kekkaku"},{"key":"B7","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1620\/tjem.233.123","article-title":"Persistently retained interferon-gamma responsiveness in individuals with a history of pulmonary tuberculosis","volume":"233","author":"Seo","year":"2014","journal-title":"Tohoku J Exp Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"l5770","DOI":"10.1136\/bmj.l5770","article-title":"Is Mycobacterium tuberculosis infection life long?","volume":"367","author":"Behr","year":"2019","journal-title":"BMJ."},{"key":"B9","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1164\/rccm.200912-1862OC","article-title":"CD4 and CD8 T-cell responses to mycobacterial antigens in African children","volume":"182","author":"Tena-Coki","year":"2010","journal-title":"Am J Respir Crit Care Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1093\/infdis\/jit265","article-title":"T-Cell immunophenotyping distinguishes active from latent tuberculosis","volume":"208","author":"Pollock","year":"2013","journal-title":"J Infect Dis."},{"key":"B11","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1016\/j.jinf.2015.07.009","article-title":"Assessment of CD27 expression as a tool for active and latent tuberculosis diagnosis","volume":"71","author":"Petruccioli","year":"2015","journal-title":"J Infect."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1827","DOI":"10.1172\/JCI77990","article-title":"Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response","volume":"125","author":"Adekambi","year":"2015","journal-title":"J Clin Invest."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1183\/09031936.00214611","article-title":"Increased frequencies of pulmonary regulatory T-cells in latent Mycobacterium tuberculosis infection","volume":"40","author":"Herzmann","year":"2012","journal-title":"Eur Respir J"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e00021","DOI":"10.1128\/CMR.00021-18","article-title":"Incipient and subclinical tuberculosis: a clinical review of early stages and progression of infection","volume":"31","author":"Drain","year":"2018","journal-title":"Clin Microbiol Rev"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e37436","DOI":"10.1371\/journal.pone.0037436","article-title":"Correlation of Mycobacterium tuberculosis specific and non-specific quantitative Th1 T-cell responses with bacillary load in a high burden setting","volume":"7","author":"Theron","year":"2012","journal-title":"PLoS ONE."},{"key":"B16","doi-asserted-by":"publisher","first-page":"19408","DOI":"10.1073\/pnas.1006298107","article-title":"Distinct functions of antigen-specific CD4 T cells during murine Mycobacterium tuberculosis infection","volume":"107","author":"Reiley","year":"2010","journal-title":"Proc Natl Acad Sci USA."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2965","DOI":"10.4049\/jimmunol.1400019","article-title":"Cutting edge: control of Mycobacterium tuberculosis infection by a subset of lung parenchyma\u2013homing CD4 T cells","volume":"192","author":"Sakai","year":"2014","journal-title":"J Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1264351","DOI":"10.3389\/fimmu.2023.1264351","article-title":"Feasibility and acceptability of undertaking postmortem studies for tuberculosis medical research in a low income country","volume":"14","author":"Ahimbisibwe","year":"2023","journal-title":"Front Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.immuni.2012.09.020","article-title":"Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets","volume":"38","author":"Sathaliyawala","year":"2013","journal-title":"Immunity."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2622","DOI":"10.1038\/s41591-022-02073-x","article-title":"Inhaled particulate accumulation with age impairs immune function and architecture in human lung lymph nodes","volume":"28","author":"Ural","year":"2022","journal-title":"Nat Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1186\/s12879-015-0904-1","article-title":"Prevalence of latent tuberculosis infection and associated risk factors in an urban African setting","volume":"15","author":"Kizza","year":"2015","journal-title":"BMC Infect Dis."},{"key":"B22","doi-asserted-by":"publisher","first-page":"818","DOI":"10.3390\/pathogens12060818","article-title":"Latent tuberculosis patients have an increased frequency of IFN-\u03b3-producing CD5+ B cells, which respond efficiently to mycobacterial proteins","volume":"12","author":"Flores-Gonzalez","year":"2023","journal-title":"Pathogens"},{"key":"B23","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1038\/s42003-024-06282-7","article-title":"B cell heterogeneity in human tuberculosis highlights compartment-specific phenotype and functional roles","volume":"7","author":"Krause","year":"2024","journal-title":"Communications Biology."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2331","DOI":"10.4049\/jimmunol.1901326","article-title":"Cutting edge: characterization of human tissue-resident memory T cells at different infection sites in patients with tuberculosis","volume":"204","author":"Yang","year":"2020","journal-title":"J Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"102009","DOI":"10.1016\/j.tube.2020.102009","article-title":"Loss of T cells expressing CD27 at the site of active tuberculosis\u2014A prospective diagnostic study","volume":"125","author":"M\u00fcller","year":"2020","journal-title":"Tuberculosis."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.3390\/pathogens11091034","article-title":"Tuberculosis treatment response monitoring by the phenotypic characterization of MTB-specific CD4+ T-cells in relation to HIV infection status","volume":"11","author":"Sitoe","year":"2022","journal-title":"Pathogens."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e1006687","DOI":"10.1371\/journal.ppat.1006687","article-title":"Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease","volume":"13","author":"Scriba","year":"2017","journal-title":"PLoS Pathog."},{"key":"B28","doi-asserted-by":"publisher","first-page":"103233","DOI":"10.1016\/j.ebiom.2021.103233","article-title":"Immune profiling of Mycobacterium tuberculosis-specific T cells in recent and remote infection","volume":"64","author":"Mpande","year":"2021","journal-title":"eBioMedicine"},{"key":"B29","doi-asserted-by":"publisher","first-page":"6619","DOI":"10.1182\/blood-2009-01-199588","article-title":"KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells","volume":"113","author":"Henson","year":"2009","journal-title":"Blood."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e1000947","DOI":"10.1371\/journal.ppat.1000947","article-title":"Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation","volume":"6","author":"Bengsch","year":"2010","journal-title":"PLoS Pathog."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e0303945","DOI":"10.1371\/journal.pone.0303945","article-title":"KLRG1-expressing CD8+ T cells are exhausted and polyfunctional in patients with chronic hepatitis B","volume":"19","author":"Wang","year":"2024","journal-title":"PLoS ONE."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.4049\/jimmunol.151.5.2426","article-title":"Regulation of CD27 expression on subsets of mature T-lymphocytes","volume":"151","author":"Hintzen","year":"1993","journal-title":"J Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"8218","DOI":"10.4049\/jimmunol.175.12.8218","article-title":"Cytomegalovirus-specific CD4+ T Cells in healthy carriers are continuously driven to replicative exhaustion1","volume":"175","author":"Fletcher","year":"2005","journal-title":"J Immunol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3091","DOI":"10.1016\/j.celrep.2017.03.007","article-title":"Th1 differentiation drives the accumulation of intravascular, non-protective CD4&T cells during tuberculosis","volume":"18","author":"Sallin","year":"2017","journal-title":"Cell Rep."}],"container-title":["Frontiers in Tuberculosis"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftubr.2025.1535945\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T06:52:43Z","timestamp":1741243963000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftubr.2025.1535945\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,6]]},"references-count":34,"alternative-id":["10.3389\/ftubr.2025.1535945"],"URL":"https:\/\/doi.org\/10.3389\/ftubr.2025.1535945","relation":{},"ISSN":["2813-7868"],"issn-type":[{"value":"2813-7868","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,6]]},"article-number":"1535945"}}