Recruitment of the cytoplasmic adaptor Grb2 to surface IgG and IgE provides antigen receptor-intrinsic costimulation to class-switched B cells.
The improved antibody responses of class-switched memory B cells depend on enhanced signaling from their B cell antigen receptors (BCRs). However, BCRs on both naive and antigen-experienced B cells use the canonical immunoglobulin-associated alpha and beta-protein signaling subunits. Here we identified a BCR isotype-specific signal-amplification mechanism. Whereas immunoglobulin M (IgM)-containing BCRs initiated intracellular signals exclusively through immunoglobulin-associated alpha- and beta-proteins, IgG- and IgE-containing BCRs also used a conserved tyrosine residue in the cytoplasmic segments of immunoglobulin heavy chains. When phosphorylated, this tyrosine recruited the adaptor Grb2, resulting in sustained protein kinase activation and prolonged generation of second messengers, which together culminated in enhanced B cell proliferation. Hence, membrane-bound IgG and IgE exert antigen recognition as well as costimulatory functions, thereby rendering memory B cells less dependent on T cell help.
Engels
Niklas
N
Institute of Cellular and Molecular Immunology, Georg-August-University Göttingen, Göttingen, Germany.
König
Lars Morten
LM
Heemann
Christina
C
Lutz
Johannes
J
Tsubata
Takeshi
T
Griep
Sebastian
S
Schrader
Verena
V
Wienands
Jürgen
J
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000502:physiology*; D006801:Humans; D017578:Immunoglobulin Class Switching; D007073:Immunoglobulin E / Q000502:physiology*; D007074:Immunoglobulin G / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D021381:Protein Transport; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D007074:Immunoglobulin G; D011947:Receptors, Antigen, B-Cell; D007073:Immunoglobulin E; D014443:Tyrosine; D002118:Calcium