PMID- 34031614 OWN - NLM STAT- MEDLINE DCOM- 20210721 LR - 20221108 IS - 1529-2916 (Electronic) IS - 1529-2908 (Print) IS - 1529-2908 (Linking) VI - 22 IP - 6 DP - 2021 Jun TI - Dynamic regulation of B cell complement signaling is integral to germinal center responses. PG - 757-768 LID - 10.1038/s41590-021-00926-0 [doi] AB - Maturation of B cells within germinal centers (GCs) generates diversified B cell pools and high-affinity B cell antigen receptors (BCRs) for pathogen clearance. Increased receptor affinity is achieved by iterative cycles of T cell-dependent, affinity-based B cell positive selection and clonal expansion by mechanisms hitherto incompletely understood. Here we found that, as part of a physiologic program, GC B cells repressed expression of decay-accelerating factor (DAF/CD55) and other complement C3 convertase regulators via BCL6, but increased the expression of C5b-9 inhibitor CD59. These changes permitted C3 cleavage on GC B cell surfaces without the formation of membrane attack complex and activated C3a- and C5a-receptor signals required for positive selection. Genetic disruption of this pathway in antigen-activated B cells by conditional transgenic DAF overexpression or deletion of C3a and C5a receptors limited the activation of mechanistic target of rapamycin (mTOR) in response to BCR-CD40 signaling, causing premature GC collapse and impaired affinity maturation. These results reveal that coordinated shifts in complement regulation within the GC provide crucial signals underlying GC B cell positive selection. FAU - Cumpelik, Arun AU - Cumpelik A AD - Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. AD - Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Heja, David AU - Heja D AD - Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. AD - Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. AD - eGenesis Inc., Cambridge, MA, USA. FAU - Hu, Yuan AU - Hu Y AD - Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. AD - Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Varano, Gabriele AU - Varano G AD - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. AD - Department of Translational Medicine, Laboratory for Advanced Therapy Technologies, University of Ferrara, Ferrara, Italy. FAU - Ordikhani, Farideh AU - Ordikhani F AD - Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. AD - Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. AD - Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Roberto, Mark P AU - Roberto MP AD - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. AD - Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - He, Zhengxiang AU - He Z AUID- ORCID: 0000-0002-8961-859X AD - Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Homann, Dirk AU - Homann D AUID- ORCID: 0000-0002-7622-5754 AD - Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Lira, Sergio A AU - Lira SA AD - Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Dominguez-Sola, David AU - Dominguez-Sola D AUID- ORCID: 0000-0001-9569-8402 AD - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. david.dominguez-sola@mssm.edu. AD - Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. david.dominguez-sola@mssm.edu. AD - Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. david.dominguez-sola@mssm.edu. AD - Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. david.dominguez-sola@mssm.edu. FAU - Heeger, Peter S AU - Heeger PS AUID- ORCID: 0000-0003-4673-6913 AD - Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. peter.heeger@mssm.edu. AD - Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. peter.heeger@mssm.edu. AD - Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. peter.heeger@mssm.edu. LA - eng GR - R01 AI071185/AI/NIAID NIH HHS/United States GR - R01 DK110352/DK/NIDDK NIH HHS/United States GR - R56 AI071185/AI/NIAID NIH HHS/United States GR - R21 AI126009/AI/NIAID NIH HHS/United States GR - T32 CA078207/CA/NCI NIH HHS/United States GR - P30 CA196521/CA/NCI NIH HHS/United States GR - R01 AI141434/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210524 PL - United States TA - Nat Immunol JT - Nature immunology JID - 100941354 RN - 0 (CD55 Antigens) RN - 0 (CD59 Antigens) RN - 0 (Proto-Oncogene Proteins c-bcl-6) RN - 0 (Receptor, Anaphylatoxin C5a) RN - 0 (Receptors, Antigen, B-Cell) RN - 0 (Receptors, Complement) RN - 0 (complement C3a receptor) RN - 80295-42-7 (Complement C3a) RN - 80295-54-1 (Complement C5a) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM CIN - Nat Immunol. 2021 Jun;22(6):673-674. PMID: 34031616 MH - Animals MH - Animals, Genetically Modified MH - B-Lymphocytes/*immunology/metabolism MH - CD55 Antigens/genetics/metabolism MH - CD59 Antigens/metabolism MH - Cell Line, Tumor MH - Clonal Hematopoiesis/immunology MH - *Complement Activation MH - Complement C3a/*metabolism MH - Complement C5a/*metabolism MH - Germinal Center/cytology/*immunology/metabolism MH - Humans MH - Lymphocyte Activation MH - Mice MH - Palatine Tonsil/cytology/pathology MH - Proto-Oncogene Proteins c-bcl-6/metabolism MH - Receptor, Anaphylatoxin C5a/genetics/metabolism MH - Receptors, Antigen, B-Cell/metabolism MH - Receptors, Complement/genetics/metabolism MH - Signal Transduction/immunology MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC8297556 MID - NIHMS1688768 COIS- Competing interests. The authors declare no competing interests. EDAT- 2021/05/26 06:00 MHDA- 2021/07/22 06:00 PMCR- 2021/11/24 CRDT- 2021/05/25 06:41 PHST- 2020/05/07 00:00 [received] PHST- 2021/03/29 00:00 [accepted] PHST- 2021/05/26 06:00 [pubmed] PHST- 2021/07/22 06:00 [medline] PHST- 2021/05/25 06:41 [entrez] PHST- 2021/11/24 00:00 [pmc-release] AID - 10.1038/s41590-021-00926-0 [pii] AID - 10.1038/s41590-021-00926-0 [doi] PST - ppublish SO - Nat Immunol. 2021 Jun;22(6):757-768. doi: 10.1038/s41590-021-00926-0. Epub 2021 May 24.