title: Antigen-affinity controls pre-germinal center B cell selection by promoting Mcl-1 induction through BAFF receptor signaling.
abstract: Upon antigen encounter, the responsive B cell pool undergoes stringent selection which eliminates cells with low B cell receptor (BCR) affinity. Already before formation of the germinal center, activated B cells of low-affinity are negatively selected in a process that is molecularly not well understood. In this study, we investigated the mechanism behind pre-GC affinity-mediated B cell selection. We applied affinity mutants of HEL antigen and found that rapidly after activation B cells become highly dependent on the cytokine BAFF. Moreover, expression of BAFF receptor CD268 is regulated in a BCR-affinity dependent fashion. High affinity responses via BAFF correlated with PI3K activation, which controlled expression of the pro-survival protein Mcl-1, and thereby increased survival. In the presence of excess BAFF, or in absence of the Mcl-1 antagonist Noxa, more low-affinity B cells survived the first two days after antigen encounter. This resulted in increased numbers of antigen-specific B cells of low affinity upon immunization and reduced the overall affinity of cells that contributed to the germinal center reaction. Our findings elucidate a crucial molecular pathway of B cell selection in the earliest phases of activation by identifying a novel link between BCR affinity and BAFF-R signaling towards Mcl-1.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, 1105AZ, Amsterdam, The Netherlands.
authors.forename: Felix M
authors.initials: FM
authors.lastname: Wensveen
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, 1105AZ, Amsterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Slinger
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, 1105AZ, Amsterdam, The Netherlands.
authors.forename: Martijn Ha
authors.initials: MH
authors.lastname: van Attekum
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, NSW 2010, Darlinghurst, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, 1105AZ, Amsterdam, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology*; D002470:Cell Survival; D008810:Mice, Inbred C57BL; D009113:Muramidase / Q000276:immunology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000941:Antigens; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C505720:Tnfsf13b protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C421864:hen egg lysozyme; D009113:Muramidase