title: Formation of BCR oligomers provides a mechanism for B cell affinity discrimination.
abstract: B cells encounter antigen over a wide affinity range, from K(A)=10(5) M(-1) to K(A)=10(10) M(-1). The strength of B cell antigen receptor (BCR) signaling in response to antigen increases with affinity, a process known as "affinity discrimination". In this work, we use a computational simulation of B cell surface dynamics and membrane-proximal signaling to show that affinity discrimination can arise from the formation of BCR oligomers. It is known that BCRs form oligomers upon encountering antigen, and that the size and rate of formation of these oligomers both increase with affinity. In our simulation, we have introduced a requirement that only BCR-antigen complexes that are part of an oligomer can engage cytoplasmic signaling molecules such as Src-family kinases. Our simulation shows that as affinity increases, BCR signaling activity increases in addition to the number of collected antigen. Our results are also consistent with the existence of an experimentally-observed threshold affinity of activation at K(A)=10(5)-10(6) M(-1) (no signaling activity below this affinity value) and affinity discrimination ceiling of K(A)=10(10) M(-1) (no affinity discrimination above this affinity value). Comparison with experiments shows that the time scale of BCR oligomer formation predicted by our model (less than 10 s) is well within the time scale of experimentally observed association of BCR with Src-family kinases (10-20 s).
authors.affiliation: Dept. of Biomedical Engineering, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Philippos K
authors.initials: PK
authors.lastname: Tsourkas
authors.forename: Das
authors.initials: D
authors.lastname: Somkanya C
authors.forename: Paul
authors.initials: P
authors.lastname: Yu-Yang
authors.forename: Wanli
authors.initials: W
authors.lastname: Liu
authors.forename: Susan K
authors.initials: SK
authors.lastname: Pierce
authors.forename: Subhadip
authors.initials: S
authors.lastname: Raychaudhuri
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000276:immunology*; D000941:Antigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D003198:Computer Simulation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007700:Kinetics; D018448:Models, Immunological; D010766:Phosphorylation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000737:chemistry* / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase; D013997:Time Factors
chemical_list: D000941:Antigens; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase