Integration of T helper and BCR signals governs enhanced plasma cell differentiation of memory B cells by regulation of CD45 phosphatase activity
Peter Szodoray,
Tor Kristian Andersen,
Julia Heinzelbecker,
John F. Imbery,
Peter C. Huszthy,
Stephanie M. Stanford,
Bjarne Bogen,
Ole B. Landsverk,
Nunzio Bottini,
Anders Tveita,
Ludvig A. Munthe,
Britt Nakken
Affiliations
Peter Szodoray
Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway; K.G. Jebsen Center for B Cell Malignancies, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Corresponding author
Tor Kristian Andersen
Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway; K.G. Jebsen Center for Influenza Vaccine Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Julia Heinzelbecker
Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway; K.G. Jebsen Center for B Cell Malignancies, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
John F. Imbery
Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway; K.G. Jebsen Center for B Cell Malignancies, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Peter C. Huszthy
Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway
Stephanie M. Stanford
Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California, San Diego, 9500 Gilman Drive MC #0656, La Jolla, CA 92093, USA
Bjarne Bogen
Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway; K.G. Jebsen Center for Influenza Vaccine Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Ole B. Landsverk
Department of Pathology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway
Nunzio Bottini
Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California, San Diego, 9500 Gilman Drive MC #0656, La Jolla, CA 92093, USA
Anders Tveita
Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway; K.G. Jebsen Center for B Cell Malignancies, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Ludvig A. Munthe
Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway; K.G. Jebsen Center for B Cell Malignancies, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Britt Nakken
Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway; K.G. Jebsen Center for B Cell Malignancies, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Summary: Humoral immunity relies on the efficient differentiation of memory B cells (MBCs) into antibody-secreting cells (ASCs). T helper (Th) signals upregulate B cell receptor (BCR) signaling by potentiating Src family kinases through increasing CD45 phosphatase activity (CD45 PA).In this study, we show that high CD45 PA in MBCs enhances BCR signaling and is essential for their effective ASC differentiation. Mechanistically, Th signals upregulate CD45 PA through intensifying the surface binding of a CD45 ligand, Galectin-1. CD45 PA works as a sensor of T cell help and defines high-affinity germinal center (GC) plasma cell (PC) precursors characterized by IRF4 expression in vivo. Increasing T cell help in vitro results in an incremental CD45 PA increase and enhances ASC differentiation by facilitating effective induction of the transcription factors IRF4 and BLIMP1. This study connects Th signals with BCR signaling through Galectin-1-dependent regulation of CD45 PA and provides a mechanism for efficient ASC differentiation of MBCs.
