title: B cell receptor signal transduction in the GC is short-circuited by high phosphatase activity.
abstract: Germinal centers (GCs) generate memory B and plasma cells, which are essential for long-lived humoral immunity. GC B cells with high-affinity B cell receptors (BCRs) are selectively expanded. To enable this selection, BCRs of such cells are thought to signal differently from those with lower affinity. We show that, surprisingly, most proliferating GC B cells did not demonstrate active BCR signaling. Rather, spontaneous and induced signaling was limited by increased phosphatase activity. Accordingly, both SH2 domain-containing phosphatase-1 (SHP-1) and SH2 domain-containing inositol 5 phosphatase were hyperphosphorylated in GC cells and remained colocalized with BCRs after ligation. Furthermore, SHP-1 was required for GC maintenance. Intriguingly, GC B cells in the cell-cycle G(2) period regained responsiveness to BCR stimulation. These data have implications for how higher-affinity B cells are selected in the GC.
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Ashraf M
authors.initials: AM
authors.lastname: Khalil
authors.forename: John C
authors.initials: JC
authors.lastname: Cambier
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D051925:CD79 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle; D015536:Down-Regulation; D018858:Germinal Center / Q000166:cytology / Q000276:immunology*; D000072181:Inositol Polyphosphate 5-Phosphatases; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018448:Models, Immunological; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase
chemical_list: D000941:Antigens; D051925:CD79 Antigens; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D010744:Phosphoric Monoester Hydrolases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; D000072181:Inositol Polyphosphate 5-Phosphatases; D002118:Calcium