Artikel ; Online: Dynamic regulation of B cell complement signaling is integral to germinal center responses.
2021 Band 22, Heft 6, Seite(n) 757–768
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- ... ...
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. |
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Mesh-Begriff(e) | Animals ; Animals, Genetically Modified ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; CD55 Antigens/genetics ; CD55 Antigens/metabolism ; CD59 Antigens/metabolism ; Cell Line, Tumor ; Clonal Hematopoiesis/immunology ; Complement Activation ; Complement C3a/metabolism ; Complement C5a/metabolism ; Germinal Center/cytology ; Germinal Center/immunology ; Germinal Center/metabolism ; Humans ; Lymphocyte Activation ; Mice ; Palatine Tonsil/cytology ; Palatine Tonsil/pathology ; Proto-Oncogene Proteins c-bcl-6/metabolism ; Receptor, Anaphylatoxin C5a/genetics ; Receptor, Anaphylatoxin C5a/metabolism ; Receptors, Antigen, B-Cell/metabolism ; Receptors, Complement/genetics ; Receptors, Complement/metabolism ; Signal Transduction/immunology ; TOR Serine-Threonine Kinases/metabolism |
Chemische Substanzen | CD55 Antigens ; CD59 Antigens ; Proto-Oncogene Proteins c-bcl-6 ; Receptor, Anaphylatoxin C5a ; Receptors, Antigen, B-Cell ; Receptors, Complement ; complement C3a receptor ; Complement C3a (80295-42-7) ; Complement C5a (80295-54-1) ; MTOR protein, human (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) |
Sprache | Englisch |
Erscheinungsdatum | 2021-05-24 |
Erscheinungsland | United States |
Dokumenttyp | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
ZDB-ID | 2016987-5 |
ISSN | 1529-2916 ; 1529-2908 |
ISSN (online) | 1529-2916 |
ISSN | 1529-2908 |
DOI | 10.1038/s41590-021-00926-0 |
Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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