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 D. Bhattacharyya, Weng Hua Khoo, Maté Biro, Tanmay Mitra, Michael Meyer‐Hermann, Patrick Bertolino, Masato Tanaka, David Hume, Peter I. Croucher, Robert Brink, Akira Nguyen, Oliver Bannard, Tri Giang Phan
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.