{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:18:49Z","timestamp":1787635129715,"version":"build-2736575974"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270020"],"award-info":[{"award-number":["82270020"]}],"id":[{"id":"10.13039\/501100001809","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>Background<\/jats:title>\n                    <jats:p>\n                      Tuberculosis (TB) remains a global public health burden, and how immune cell subsets regulate host anti-TB immunity and disease progression remains incompletely understood. While previous studies have focused on single-positive (SP) T cells (CD4\n                      <jats:sup>+<\/jats:sup>\n                      or CD8\n                      <jats:sup>+<\/jats:sup>\n                      ) in TB pathogenesis, the association between CD4\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      double-positive (DP) T cells and TB susceptibility, severity, and treatment outcomes have not been fully elucidated. This study aimed to investigate the relationship between DP T cells and other immune cell subsets with TB, and to explore the potential diagnostic and prognostic value of DP T cells in active TB.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A Genome-Wide Association Study (GWAS) was conducted to analyze 731 immune cell traits and a dataset encompassing 895 patients with TB. Subsequently, a cohort including 647 patients with active TB and 632 healthy controls was used to verify the findings of Mendelian randomization (MR). The correlation between the percentage of DP T cells in lymphocytes and TB severity, treatment efficacy, and\n                      <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                      (Mtb)-specific IFN-\u03b3 production was evaluated. Finally, a random forest model incorporating the percentage of DP T cells in leukocytes and other peripheral blood parameters was constructed to distinguish severe from mild active TB.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MR analysis suggested potential causal links between the percentage of DP T cells among peripheral leukocytes and TB status. Clinical sample validation showed that the percentage of peripheral DP T cell among leukocytes was significantly lower in patients with active TB than in healthy controls (P &amp;lt; 0.001), and was inversely correlated with disease severity. Additionally, the percentage of DP T cells in leukocytes was positively correlated with Mtb-specific antigen-stimulated IFN-\u03b3 production. Flow cytometric analysis demonstrated that DP T cells had a significantly higher frequency of IFN-\u03b3-expressing cells compared to CD8\n                      <jats:sup>+<\/jats:sup>\n                      SP T cells (P &amp;lt; 0.001). The constructed random forest model effectively distinguished severe from mild TB, with good diagnostic performance (AUC\u00a0=\u00a00.985).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings indicate that DP T cells are closely associated with TB severity, and are positively associated with Mtb-specific IFN-\u03b3 response. The percentage of peripheral DP T cells in leukocytes could serve as a potential non-invasive biomarker for TB severity stratification.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1887199","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T04:23:50Z","timestamp":1787631830000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CD4+CD8+ double-positive T cells are associated with severity of tuberculosis"],"prefix":"10.3389","volume":"16","author":[{"given":"Bingfen","family":"Yang","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Institute of Tuberculosis Research, Senior Department of Tuberculosis, the Eighth Medical Center of Chinese People's Liberation Army (PLA) General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjuan","family":"An","sequence":"additional","affiliation":[{"name":"Tuberculosis Control Team, Senior Department of Tuberculosis, The Eighth Medical Center of PLA General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Outpatient Department, Senior Department of Tuberculosis, the Eighth Medical Center of PLA General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Cao","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Institute of Tuberculosis Research, Senior Department of Tuberculosis, the Eighth Medical Center of Chinese People's Liberation Army (PLA) General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinwen","family":"Su","sequence":"additional","affiliation":[{"name":"Institute of Research, Beijing Key Laboratory of Organ Transplantation and Immune Regulation, Senior Department of Respiratory and Critical Care Medicine, the Eighth Medical Center of PLA General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoou","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Institute of Tuberculosis Research, Senior Department of Tuberculosis, the Eighth Medical Center of Chinese People's Liberation Army (PLA) General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinping","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Institute of Tuberculosis Research, Senior Department of Tuberculosis, the Eighth Medical Center of Chinese People's Liberation Army (PLA) General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinjing","family":"Wang","sequence":"additional","affiliation":[{"name":"Outpatient Department, Senior Department of Tuberculosis, the Eighth Medical Center of PLA General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Jiang","sequence":"additional","affiliation":[{"name":"Intensive Care Unit, Senior Department of Tuberculosis, the Eighth Medical Center of PLA General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxing","family":"Cheng","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Institute of Tuberculosis Research, Senior Department of Tuberculosis, the Eighth Medical Center of Chinese People's Liberation Army (PLA) General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1038\/nature09247","article-title":"An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis","volume":"466","author":"Berry","year":"2010","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2281","DOI":"10.4049\/jimmunol.134.4.2281","article-title":"Coexpression of T4 and T8 on peripheral blood T cells demonstrated by two-color fluorescence flow cytometry","volume":"134","author":"Blue","year":"1985","journal-title":"J. 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