{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T10:25:25Z","timestamp":1777890325104,"version":"3.51.4"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Asymptomatic individuals with negative Interferon-\u03b3 release assay (IGRA) and tuberculin skin test (TST) results are often labeled as tuberculosis-unexposed individuals. We hypothesize that flow cytometric (FC) detection of antigen-stimulated T-cells in peripheral blood can differentiate IGRA(-)\/TST(-) individuals with and without prior potential\n                      <jats:italic>M. tuberculosis<\/jats:italic>\n                      (Mtb) exposure.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used FC multiparameter profiling of T-cell activation markers in TST\/IGRA-negative individuals at risk for Mtb exposure and in unexposed controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We studied 54 IGRA(-)\/TST(-) subjects, including 27 individuals at risk for prior Mtb exposure. While quantitative IGRA results were negative in all patients, FC profiling of CD3\/CD4\n                      <jats:sup>+<\/jats:sup>\n                      IFN-\u03b3\n                      <jats:sup>+<\/jats:sup>\n                      HLA-DR\n                      <jats:sup>+<\/jats:sup>\n                      T-cells after stimulation with a pool of Mtb-specific region of difference-1 (RD1) peptides, mycobacterial (PPD and MTB300), or\n                      <jats:italic>Candida<\/jats:italic>\n                      antigens, statistically differentiated between unexposed and potentially exposed individuals (P&amp;lt;0.05). ROC analysis showed PPD and RD1 peptides responses had AUCs &amp;gt;0.7 (sensitivity of 55.5\u201374% and specificity of 66.6\u201385.1%). The presence of a polyfunctional RD1-reactive CD3\/CD8\n                      <jats:sup>+<\/jats:sup>\n                      IFN-\u03b3\n                      <jats:sup>+<\/jats:sup>\n                      TNF-\u03b1\n                      <jats:sup>+<\/jats:sup>\n                      T-cell subset also significantly differentiated these groups (AUC 0.66). Other T-cell markers demonstrated no significant differences.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      FC detection of antigen-specific IFN-\u03b3\n                      <jats:sup>+<\/jats:sup>\n                      HLA-DR\n                      <jats:sup>+<\/jats:sup>\n                      CD4+T-cells and IFN-\u03b3\n                      <jats:sup>+<\/jats:sup>\n                      TNF-\u03b1\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cells can differentiate IGRA(-)\/TST(-) individuals at risk of Mtb exposure from unexposed controls. Further validation is needed to determine whether this immunoprofiling approach can improve detection of Mtb infections and identification of unexposed individuals for future biomarker studies and vaccine trails.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1837269","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T05:35:32Z","timestamp":1777613732000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multiparameter antigen-specific immunoprofiling in subjects with negative IGRA and TST results with potential M. tuberculosis exposures"],"prefix":"10.3389","volume":"16","author":[{"given":"Balaji","family":"Pathakumari","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis E.","family":"Gutierrez","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaji Ahmed","family":"Faisal","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro Arias","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kale","family":"Daniel","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia P.","family":"Van Keulen","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather R.","family":"Hilgart","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manik R.","family":"Reddy","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Michigan","place":["Ann Arbor, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elitza","family":"Theel","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Laniado-Laborin","sequence":"additional","affiliation":[{"name":"Clinica y Laboratorio de Tuberculosis, Facultad de Medicina y Psicologia, Hospital General Tijuana, Universidad Autonoma de Baja California, ISESALUD","place":["Tijuana, Baja California, Mexico"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy M.","family":"Clain","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobias","family":"Peikert","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan C.","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Michigan","place":["Ann Arbor, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricio","family":"Escalante","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1093\/cid\/ciab269","article-title":"Resistance to Mycobacterium tuberculosis infection among household contacts: A multinational study","volume":"73","author":"Baliashvili","year":"2021","journal-title":"Clin. 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