Abstract
B lymphocytes are activated by many different antigens to produce specific antibodies protecting higher organisms from infection. To detect its cognate antigen, each B cell contains up to 120,000 B-cell antigen receptor (BCR) complexes on its cell surface. How these abundant receptors stay silent on resting B cells and how they can be activated by a molecularly diverse set of ligands is poorly understood. Here we show, with the use of a quantitative bifluorescence complementation assay (BiFC), that the BCR has an intrinsic ability to form oligomers on the surface of living cells. A BCR mutant that fails to form oligomers is more active and cannot be expressed stably on the B-cell surface, whereas BiFC-stabilized BCR oligomers are less active and more strongly expressed on the surface. We propose that oligomers are the autoinhibited form of the BCR and that it is the shift from closed BCR oligomers to clustered monomers that drives B-cell activation in a way that is independent of the structural input from the antigen.
MeSH Terms
Animals
B-Lymphocytes/cytology,immunology,metabolism
Cell Line
Drosophila melanogaster/cytology
Immunoglobulin D/genetics,immunology
Lymphocyte Activation/immunology
Protein Multimerization/immunology
Receptors, Antigen, B-Cell/antagonists & inhibitors,chemistry,immunology,metabolism
Chemicals
Immunoglobulin D
Receptors, Antigen, B-Cell
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Yang Jianying
Centre for Biological Signalling Studies BIOSS, Albert-Ludwigs-Universität Freiburg, Department of Molecular Immunology, Faculty of Biology, Albert-Ludwigs-Universität Freiburg and Max Planck Institute for Immunobiology, Stübeweg 51, 79108 Freiburg, Germany.
Reth Michael
References (31)
31 references, click to expand
-
The initiation of antigen-induced B cell antigen receptor signaling viewed in living cells by fluorescence resonance energy transfer.
Nat Immunol. 2005 Nov;6(11):1168-76
PMID: 16200067
-
Monomeric and oligomeric complexes of the B cell antigen receptor.
Immunity. 2000 Jul;13(1):5-14
PMID: 10933390
-
Antigen receptor function in chronic lymphocytic leukemia B cells.
Leuk Lymphoma. 1996 Dec;24(1-2):27-33
PMID: 9049959
-
Survival of resting mature B lymphocytes depends on BCR signaling via the Igalpha/beta heterodimer.
Cell. 2004 Jun 11;117(6):787-800
PMID: 15186779
-
Defective assembly of the B-cell receptor chains accounts for its low expression in B-chronic lymphocytic leukaemia.
Br J Haematol. 2002 Sep;118(4):976-85
PMID: 12199775
-
Simultaneous visualization of multiple protein interactions in living cells using multicolor fluorescence complementation analysis.
Nat Biotechnol. 2003 May;21(5):539-45
PMID: 12692560
-
B cell receptor signaling in human systemic lupus erythematosus.
Curr Opin Rheumatol. 2006 Sep;18(5):451-5
PMID: 16896281
-
Monovalent ligation of the B cell receptor induces receptor activation but fails to promote antigen presentation.
Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3327-32
PMID: 16492756
-
Independent trafficking of Ig-alpha/Ig-beta and mu-heavy chain is facilitated by dissociation of the B cell antigen receptor complex.
J Immunol. 2005 Jul 1;175(1):147-54
PMID: 15972641
-
Conventional light chains inhibit the autonomous signaling capacity of the B cell receptor.
Immunity. 2007 Mar;26(3):323-33
PMID: 17331747
-
The membrane skeleton controls diffusion dynamics and signaling through the B cell receptor.
Immunity. 2010 Feb 26;32(2):187-99
PMID: 20171124
-
Identification of disulfide bonds in the Ig-alpha/Ig-beta component of the B cell antigen receptor using the Drosophila S2 cell reconstitution system.
Int Immunol. 2006 Sep;18(9):1385-96
PMID: 16877534
-
Full activation of the T cell receptor requires both clustering and conformational changes at CD3.
Immunity. 2007 Jan;26(1):43-54
PMID: 17188005
-
Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation.
Cell. 2002 Jun 28;109(7):901-12
PMID: 12110186
-
Bimolecular fluorescence complementation (BiFC) analysis as a probe of protein interactions in living cells.
Annu Rev Biophys. 2008;37:465-87
PMID: 18573091
-
Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response.
J Exp Med. 2005 Aug 15;202(4):493-503
PMID: 16087711
-
Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop.
Mol Cell. 2002 Nov;10(5):1057-69
PMID: 12453414
-
New insights into the early molecular events underlying B cell activation.
Immunity. 2008 May;28(5):609-19
PMID: 18482567
-
Normal Syk protein level but abnormal tyrosine phosphorylation in B-CLL cells.
Leukemia. 1997 Nov;11(11):1921-8
PMID: 9369427
-
B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor.
Annu Rev Immunol. 2003;21:841-94
PMID: 12615894
-
ITAM-mediated tonic signalling through pre-BCR and BCR complexes.
Nat Rev Immunol. 2006 Apr;6(4):283-94
PMID: 16557260
-
TCR and Lat are expressed on separate protein islands on T cell membranes and concatenate during activation.
Nat Immunol. 2010 Jan;11(1):90-6
PMID: 20010844
-
The B-cell antigen receptor of the five immunoglobulin classes.
Nature. 1991 Aug 29;352(6338):777-81
PMID: 1881434
-
High-sensitivity detection and quantitative analysis of native protein-protein interactions and multiprotein complexes by flow cytometry.
Sci STKE. 2007 Jun 05;2007(389):pl2
PMID: 17551170
-
Viewing the antigen-induced initiation of B-cell activation in living cells.
Immunol Rev. 2008 Feb;221:64-76
PMID: 18275475
-
Altered T and B lymphocyte signaling pathways in lupus.
Autoimmun Rev. 2009 Jan;8(3):179-83
PMID: 18721908
-
The Ig-alpha ITAM is required for efficient differentiation but not proliferation of pre-B cells.
Eur J Immunol. 2007 Jan;37(1):252-60
PMID: 17163454
-
Conformational plasticity and navigation of signaling proteins in antigen-activated B lymphocytes.
Adv Immunol. 2008;97:251-81
PMID: 18501772
-
Activation of extracellular signal-regulated kinase through B-cell antigen receptor in B-cell chronic lymphocytic leukemia.
Int J Hematol. 2002 Jun;75(5):508-13
PMID: 12095152
-
Oligomeric antigen receptors: a new view on signaling for the selection of lymphocytes.
Trends Immunol. 2001 Jul;22(7):356-60
PMID: 11429318
-
Visualization of interactions among bZIP and Rel family proteins in living cells using bimolecular fluorescence complementation.
Mol Cell. 2002 Apr;9(4):789-98
PMID: 11983170