Apoptotic cell fragments locally activate tingible body macrophages in the germinal center

Abigail K Grootveld; Wunna Kyaw; Veera Panova; Angelica W Y Lau; Emily Ashwin; Guillaume Seuzaret; Rama Dhenni; Nayan Deger Bhattacharyya; Weng Hua Khoo; Maté Biro; Tanmay Mitra; Michael Meyer-Hermann; Patrick Bertolino; Masato Tanaka; David A Hume; Peter I Croucher; Robert Brink; Akira Nguyen; Oliver Bannard; Tri Giang Phan

doi:10.1016/j.cell.2023.02.004

Apoptotic cell fragments locally activate tingible body macrophages in the germinal center

Cell. 2023 Mar 16;186(6):1144-1161.e18. doi: 10.1016/j.cell.2023.02.004. Epub 2023 Mar 2.

Authors

Abigail K Grootveld¹, Wunna Kyaw², Veera Panova³, Angelica W Y Lau², Emily Ashwin⁴, Guillaume Seuzaret⁵, Rama Dhenni², Nayan Deger Bhattacharyya⁶, Weng Hua Khoo², Maté Biro⁷, Tanmay Mitra⁸, Michael Meyer-Hermann⁹, Patrick Bertolino¹⁰, Masato Tanaka¹¹, David A Hume¹², Peter I Croucher², Robert Brink², Akira Nguyen², Oliver Bannard¹³, Tri Giang Phan¹⁴

Affiliations

¹ Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; St Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia. Electronic address: [email protected].
² Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; 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 Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; Department of Biology and Biochemistry, University of Bath, Bath, UK.
⁵ Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; Département de Biologie, Université de Lyon, Lyon, France.
⁶ Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia.
⁷ EMBL Australia, Single Molecule Science Node, School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia.
⁸ Department of Systems Biology and Braunschweig Integrated Center for Systems Biology (BRICS), Helmholtz Center for Infection Research, Rebenring 56, D-38106 Braunschweig, Germany.
⁹ Department of Systems Biology and Braunschweig Integrated Center for Systems Biology (BRICS), Helmholtz Center for Infection Research, Rebenring 56, D-38106 Braunschweig, Germany; Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig, Germany.
¹⁰ Centenary Institute and University of Sydney, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
¹¹ Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
¹² Mater Research Institute, University of Queensland, Brisbane, QLD, Australia.
¹³ MRC Human Immunology Unit, Nuffield Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. Electronic address: [email protected].
¹⁴ Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; St Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia. Electronic address: [email protected].

Abstract

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.

Keywords: B cells; apoptosis; autoimmunity; germinal center; tingible body macrophages.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
B-Lymphocytes
Germinal Center*
Lymph Nodes* / cytology
Macrophages* / cytology
Macrophages* / metabolism

Abstract

Publication types

MeSH terms

Grants and funding