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 language | English |
|---|---|
| Pages (from-to) | 1144-1161.e18 |
| Journal | Cell |
| Volume | 186 |
| Issue number | 6 |
| Early online date | 2 Mar 2023 |
| DOIs | |
| Publication status | Published - 16 Mar 2023 |
| Externally published | Yes |
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.
Funding
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 ]. For the purpose of Open Access, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission. We thank the Linda Dansereau and the ACRF INCITe Center for Intravital Imaging, and Eric Lim, Hira Saeed, and staff at the Garvan-Weizmann Center for Cellular Genomics. We thank M. Hill and H. Sjoberg for shielded irradiation expertise, and C. Lagerholm, J. Koth, and C. Lai (Wolfson Imaging Center, Oxford) for imaging assistance. 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]. For the purpose of Open Access, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission. We thank the Linda Dansereau and the ACRF INCITe Center for Intravital Imaging, and Eric Lim, Hira Saeed, and staff at the Garvan-Weizmann Center for Cellular Genomics. We thank M. Hill and H. Sjoberg for shielded irradiation expertise, and C. Lagerholm, J. Koth, and C. Lai (Wolfson Imaging Center, Oxford) for imaging assistance. O.B. and T.G.P. conceived and supervised the study. A.K.G. W.K. V.P. and A.N. planned experiments. A.K.G. W.K. V.P. A.W.Y.L. E.A. G.S. R.D. and N.D.B. performed experiments. V.P. planned, performed, and analyzed all irradiation, DT killing, CCR2, CX3CR1, and CD68 reporter experiments, supervised by O.B. A.N. designed and analyzed scRNA-seq. A.K.G. W.H.K. and A.N. performed scRNA-seq. W.K. performed image analysis and mathematical modeling with input from M.B. T.M. and M.M.-H. A.K.G. W.K. V.P. A.N. D.H. O.B. and T.G.P. wrote the manuscript with input from all authors. The authors declare no competing interests.
Keywords
- apoptosis
- autoimmunity
- B cells
- germinal center
- tingible body macrophages
ASJC Scopus subject areas
- General Biochemistry,Genetics and Molecular Biology