The constant region of the membrane immunoglobulin mediates B cell-receptor clustering and signaling in response to membrane antigens.
B cells are activated in vivo after the B cell receptors (BCRs) bind to antigens captured on the surfaces of antigen-presenting cells. Antigen binding results in BCR microclustering and signaling; however, the molecular nature of the signaling-active BCR clusters is not well understood. Using single-molecule imaging techniques, we provide evidence that within microclusters, the binding of monovalent membrane antigens results in the assembly of immobile signaling-active BCR oligomers. The oligomerization depends on interactions between the membrane-proximal Cmicro4 domains of the membrane immunoglobulin that are both necessary and sufficient for assembly. Antigen-bound BCRs that lacked the Cmicro4 domain failed to cluster and signal, and conversely, Cmicro4 domains alone clustered spontaneously and activated B cells. These results support a unique mechanism for the initiation of BCR signaling in which antigen binding induces a conformational change in the Fc portion of the BCR, revealing an interface that promotes BCR clustering.
Tolar
Pavel
P
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
Hanna
Joseph
J
Krueger
Peter D
PD
Pierce
Susan K
SK
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002462:Cell Membrane / Q000502:physiology*; D007127:Immunoglobulin Constant Regions / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009592:Nitrohydroxyiodophenylacetate / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction; D000072377:Syk Kinase
D007127:Immunoglobulin Constant Regions; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D018799:Intercellular Adhesion Molecule-1; D009592:Nitrohydroxyiodophenylacetate; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse