Dynamic regulation of B cell complement signaling is integral to germinal center responses

Nat Immunol. 2021 Jun;22(6):757-768. doi: 10.1038/s41590-021-00926-0. | PubMed

Arun Cumpelik^1,2, David Heja^1,2,3, Yuan Hu^1,2, Gabriele Varano^4,5, Farideh Ordikhani^1,2,6, Mark P Roberto^4,7, Zhengxiang He⁸, Dirk Homann⁸, Sergio A Lira⁸, David Dominguez-Sola^9,10,11,12, Peter S Heeger^13,14,15

1. Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2. Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3. eGenesis Inc., Cambridge, MA, USA.
4. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5. Department of Translational Medicine, Laboratory for Advanced Therapy Technologies, University of Ferrara, Ferrara, Italy.
6. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. david.dominguez-sola@mssm.edu.
10. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. david.dominguez-sola@mssm.edu.
11. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. david.dominguez-sola@mssm.edu.
12. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. david.dominguez-sola@mssm.edu.
13. Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. peter.heeger@mssm.edu.
14. Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. peter.heeger@mssm.edu.
15. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. peter.heeger@mssm.edu.

Abstract

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.

Presented By Arun Cumpelik