Enhanced BCR signaling inflicts early plasmablast and germinal center B cell death
Juan Carlos Yam-Puc,
Lingling Zhang,
Raul A Maqueda-Alfaro,
Laura Garcia-Ibanez,
Yang Zhang,
Jessica Davies,
Yotis A Senis,
Michael Snaith,
Kai-Michael Toellner
Affiliations
Juan Carlos Yam-Puc
Institute of Immunology and Immunotherapy, College of Medical & Dental Sciences/IBR, University of Birmingham, Birmingham, B15 2TT, UK; Corresponding author
Lingling Zhang
Institute of Immunology and Immunotherapy, College of Medical & Dental Sciences/IBR, University of Birmingham, Birmingham, B15 2TT, UK
Raul A Maqueda-Alfaro
Center for Advanced Research, The National Polytechnic Institute, Cinvestav-IPN, Mexico City, 07340, Mexico
Laura Garcia-Ibanez
Institute of Immunology and Immunotherapy, College of Medical & Dental Sciences/IBR, University of Birmingham, Birmingham, B15 2TT, UK
Yang Zhang
Institute of Immunology and Immunotherapy, College of Medical & Dental Sciences/IBR, University of Birmingham, Birmingham, B15 2TT, UK
Jessica Davies
Institute of Immunology and Immunotherapy, College of Medical & Dental Sciences/IBR, University of Birmingham, Birmingham, B15 2TT, UK
Yotis A Senis
Université de Strasbourg, Institut National de la Santé et de la Recherche Médicale, Etablissement Français du Sang Grand Est, Unité Mixte de Recherche-S 1255, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France
Michael Snaith
AstraZeneca Medimmune Cambridge, Antibody Discovery and Protein Engineering, Cambridge, UK
Kai-Michael Toellner
Institute of Immunology and Immunotherapy, College of Medical & Dental Sciences/IBR, University of Birmingham, Birmingham, B15 2TT, UK; Corresponding author
Summary: It is still not clear how B cell receptor (BCR) signaling intensity affects plasma cell (PC) and germinal center (GC) B cell differentiation. We generated Cγ1Cre/wtPtpn6fl/fl mice where SHP-1, a negative regulator of BCR signaling, is deleted rapidly after B cell activation. Although immunization with T-dependent antigens increased BCR signaling, it led to PC reduction and increased apoptosis. Dependent on the antigen, the early GC B cell response was equally reduced and apoptosis increased. At the same time, a higher proportion of GC B cells expressed cMYC, suggesting GC B cell-Tfh cell interactions may be increased. GC B cell numbers returned to normal at later stages, whereas affinity maturation was suppressed in the long term. This confirms that BCR signaling not only directs affinity-dependent B cell selection but also, without adequate further stimulation, can inflict cell death, which may be important for the maintenance of B cell tolerance.
