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

doi:10.1016/j.celrep.2021.109525

Integration of T helper and BCR signals governs enhanced plasma cell differentiation of memory B cells by regulation of CD45 phosphatase activity

Cell Rep. 2021 Aug 10;36(6):109525. doi: 10.1016/j.celrep.2021.109525.

Affiliations

¹ 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. Electronic address: peter.szodoray@medisin.uio.no.
² 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.
³ 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.
⁴ Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway.
⁵ Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California, San Diego, 9500 Gilman Drive MC #0656, La Jolla, CA 92093, USA.
⁶ Department of Pathology, University of Oslo and Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway.

Abstract

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.

Keywords: B cell memory; B cell receptor signaling; BLIMP1; CD45 phosphatase activity; Galectin-1; IRF4; T cell help; antibody-secreting cell.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibody Formation
B-Lymphocytes / cytology*
CD40 Ligand / metabolism
Cell Differentiation / immunology*
Female
Galectin 1 / metabolism
Germinal Center / cytology
Humans
Immunologic Memory*
Leukocyte Common Antigens / metabolism*
Lymphocyte Subsets / metabolism
Mice
Mice, Inbred BALB C
Plasma Cells / cytology*
Receptors, Antigen, B-Cell / metabolism*
T-Lymphocytes, Helper-Inducer / metabolism*
Up-Regulation

Substances

Galectin 1
Receptors, Antigen, B-Cell
CD40 Ligand
Leukocyte Common Antigens

Grants and funding

R01 AI070544/AI/NIAID NIH HHS/United States