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

• Published in: Nature Immunology Vol. 22; no. 6; pp. 757 - 768
• Main Authors: Cumpelik, Arun, Heja, David, Hu, Yuan, Varano, Gabriele, Ordikhani, Farideh, Roberto, Mark P., He, Zhengxiang, Homann, Dirk, Lira, Sergio A., Dominguez-Sola, David, Heeger, Peter S.
• Format: Journal Article
• Language: English
• Published: New York Springer Science and Business Media LLC 01.06.2021; Nature Publishing Group US; Nature Publishing Group
• Subjects: 631/250/2152/2153/1982; 631/250/2501; Affinity; Animals; Animals, B-Lymphocytes, CD55 Antigens, CD59 Antigens, Clonal Hematopoiesis, Lymphocyte Activation; Animals, Genetically Modified; Antigens; B cells; B-cell receptor; B-Lymphocytes; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Bcl-6 protein; Biomedical and Life Sciences; Biomedicine; CD40 antigen; CD55 Antigens; CD55 Antigens - genetics; CD55 Antigens - metabolism; CD59 antigen; CD59 Antigens; CD59 Antigens - metabolism; Cell activation; Cell Line, Tumor; Cellular signal transduction; Clonal Hematopoiesis; Clonal Hematopoiesis - immunology; Clonal selection; Complement (Immunology); Complement Activation; Complement C3a; Complement C3a - metabolism; Complement C5a; Complement C5a - metabolism; Complement component C3; Complement component C5a; Complement regulatory proteins; Decay-accelerating factor; Genetic aspects; Germinal Center; Germinal Center - cytology; Germinal Center - immunology; Germinal Center - metabolism; Germinal centers; Health aspects; Humans; Immunology; Infectious Diseases; Lymphocyte Activation; Lymphocytes B; Lymphocytes T; Lymphoid tissue; Membrane attack complex; Mice; Palatine Tonsil; Palatine Tonsil - cytology; Palatine Tonsil - pathology; Physiological aspects; Positive selection; Proto-Oncogene Proteins c-bcl-6; Proto-Oncogene Proteins c-bcl-6 - metabolism; Rapamycin; Receptor, Anaphylatoxin C5a; Receptor, Anaphylatoxin C5a - genetics; Receptor, Anaphylatoxin C5a - metabolism; Receptors, Antigen, B-Cell; Receptors, Antigen, B-Cell - metabolism; Receptors, Complement; Receptors, Complement - genetics; Receptors, Complement - metabolism; Signal Transduction; Signal Transduction - immunology; TOR protein; TOR Serine-Threonine Kinases; TOR Serine-Threonine Kinases - metabolism; Transcription factors; United States
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-021-00926-0

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. Heeger and colleagues report that activated B cells dynamically regulate the expression of complement regulatory proteins via the transcription factor BCL6. C3 convertase activity and C3aR1–C5aR1 signaling were both necessary for optimal B cell activation and germinal center formation.