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Here, we employed whole-slide spatial proteomics to map immune cell organization in TB-affected human lung tissues. Our analysis revealed pronounced spatial segregation of major immune cell populations in non-necrotizing TB lesions. At the tissue level, macrophages and lymphocytes formed distinct cellular communities associated with specific pathological features. At the lesion level, macrophages and B cells showed an inverse relationship in both abundance and spatial distribution. Proinflammatory T cells preferentially accumulated in macrophage-rich lesions but remained largely separated from macrophages. Interestingly, lesions exhibiting clear segregation between T cells and macrophages were more common in subclinical TB than in active disease. These findings suggest that spatial isolation of macrophages from effector lymphocytes may help temper inflammation and potentially prevent lesion progression to necrosis, while also enabling immune evasion by\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  .\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>Xiao et al. reveal spatial segregation of immune cells in TB-lung tissue and link the microenvironmental dynamics to disease states of tuberculosis.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.04.11.648467","type":"posted-content","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T01:10:11Z","timestamp":1744593011000},"source":"Crossref","is-referenced-by-count":2,"title":["Tissue-wide profiling of human lungs reveals spatial sequestration of macrophages in tuberculosis"],"prefix":"10.64898","author":[{"given":"Wei","family":"Xiao","sequence":"first","affiliation":[{"name":"School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia"},{"name":"Charles Perkins Centre, The University of Sydney, Sydney, Australia, The University of Sydney, Sydney, Australia"},{"name":"Sydney Institute of Infectious Disease, The University of Sydney, Sydney, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew J.","family":"Sawyer","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia"},{"name":"Charles Perkins Centre, The University of Sydney, Sydney, Australia, The University of Sydney, Sydney, Australia"},{"name":"Centenary Institute, The University of Sydney, Sydney, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siwei","family":"Mo","sequence":"additional","affiliation":[{"name":"Guangdong Key Laboratory of Infection Immunity and Inflammation, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyu","family":"Bai","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia"},{"name":"Charles Perkins Centre, The University of Sydney, Sydney, Australia, The University of Sydney, Sydney, Australia"},{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinzhu","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Fielder","sequence":"additional","affiliation":[{"name":"Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangdong Key Laboratory of Infection Immunity and Inflammation, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youchao","family":"Dai","sequence":"additional","affiliation":[{"name":"Guangdong Key Laboratory of Infection Immunity and Inflammation, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianting","family":"Yang","sequence":"additional","affiliation":[{"name":"Guangdong Key Lab for Diagnosis and Treatment of Emerging Infectious Diseases, Shenzhen Third People\u2019s Hospital, Shenzhen, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1363-2328","authenticated-orcid":false,"given":"Yi","family":"Cai","sequence":"additional","affiliation":[{"name":"Guangdong Key Laboratory of Infection Immunity and Inflammation, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guanggui","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; 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