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

Research output: Contribution to journalArticlepeer-review

12 Citations (SciVal)

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.

Original languageEnglish
Pages (from-to)1144-1161.e18
JournalCell
Volume186
Issue number6
Early online date2 Mar 2023
DOIs
Publication statusPublished - 16 Mar 2023
Externally publishedYes

Bibliographical note

Funding Information:
This project is supported by the Australian National Health and Medical Research Council (NHMRC) Ideas Grant APPID2003662. T.G.P. and P.I.C. and this work are supported by Mrs. Janice Gibb and the Ernest Heine Family Foundation. P.I.C. (APPID2009010), R.B. (APPID2008356), and T.G.P. (APPID1155678) are supported by Investigator Grants and Fellowships from the NHMRC. A.K.G. and W.K. are supported by an Australian Government Research Training Scholarship and R.D. by a UNSW Scientia PhD Scholarship. O.B. and this study were funded by The Wellcome Trust (220219/Z/20/Z) and by the Medical Research Council (MRC) through core funding to the MRC Human Immunology Unit and MRC WIMM. This research was funded in whole, or in part, by the Wellcome Trust [220219/Z/20/Z].

Data and code availability
- Single-cell RNA-seq data have been deposited at GEO and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. Intravital imaging, confocal microscopy and FACS data reported in this paper will be shared by the lead contact upon request.
- All original code has been deposited at Zenodo and is publicly available as of the date of publication. DOIs are listed in the key resources table.
- Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Keywords

  • apoptosis
  • autoimmunity
  • B cells
  • germinal center
  • tingible body macrophages

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology

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