부산대학교 도서관

Keywords germinal center; B cells; apoptosis; tingible body macrophages; autoimmunity Highlights * TBMs are lymph node-resident, CD169-lineage, CSF1R-blockade-resistant macrophages * TBM precursors in the follicle are activated by local cell death * TBMs are stationary and uniformly dispersed throughout the germinal center * TBMs use cellular processes to search for and capture motile apoptotic cell fragments Summary Germinal centers (GCs) that form within lymphoid follicles during antibody responses are sites of massive cell death. Tingible body macrophages (TBMs) are tasked with apoptotic cell clearance to prevent secondary necrosis and autoimmune activation by intracellular self antigens. We show by multiple redundant and complementary methods that TBMs derive from a lymph node-resident, CD169-lineage, CSF1R-blockade-resistant precursor that is prepositioned in the follicle. Non-migratory TBMs use cytoplasmic processes to chase and capture migrating dead cell fragments using a 'lazy' search strategy. Follicular macrophages activated by the presence of nearby apoptotic cells can mature into TBMs in the absence of GCs. Single-cell transcriptomics identified a TBM cell cluster in immunized lymph nodes which upregulated genes involved in apoptotic cell clearance. Thus, apoptotic B cells in early GCs trigger activation and maturation of follicular macrophages into classical TBMs to clear apoptotic debris and prevent antibody-mediated autoimmune diseases. Author Affiliation: (1) Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia (2) St Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia (3) MRC Human Immunology Unit, Nuffield Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK (4) Department of Biology and Biochemistry, University of Bath, Bath, UK (5) Département de Biologie, Université de Lyon, Lyon, France (6) EMBL Australia, Single Molecule Science Node, School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia (7) Department of Systems Biology and Braunschweig Integrated Center for Systems Biology (BRICS), Helmholtz Center for Infection Research, Rebenring 56, D-38106 Braunschweig, Germany (8) Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig, Germany (9) Centenary Institute and University of Sydney, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia (10) Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (11) Mater Research Institute, University of Queensland, Brisbane, QLD, Australia * Corresponding author Article History: Received 23 September 2022; Revised 4 January 2023; Accepted 31 January 2023 (miscellaneous) Published: March 2, 2023 (footnote)12 These authors contributed equally (footnote)13 Lead contact Byline: Abigail K. Grootveld [a.grootveld@garvan.org.au] (1,2,12,*), Wunna Kyaw (1,2,12), Veera Panova (3), Angelica W.Y. Lau (1,2), Emily Ashwin (1,4), Guillaume Seuzaret (1,5), Rama Dhenni (1,2), Nayan Deger Bhattacharyya (1), Weng Hua Khoo (1,2), Maté Biro (6), Tanmay Mitra (7), Michael Meyer-Hermann (7,8), Patrick Bertolino (9), Masato Tanaka (10), David A. Hume (11), Peter I. Croucher (1,2), Robert Brink (1,2), Akira Nguyen (1,2), Oliver Bannard [oliver.bannard@ndm.ox.ac.uk] (3,**), Tri Giang Phan [t.phan@garvan.org.au] (1,2,13,***)