title: B-cell receptor signal strength influences terminal differentiation.
abstract: B-cell terminal differentiation into antibody secreting plasma cells (PCs) features a transcriptional shift driven by the activation of plasma cell lineage determinants such as Blimp-1 and Xbp-1, together with the extinction of Pax5. Little is known about the signals inducing this change in transcriptional networks and the role of the B-cell receptor (BCR) in terminal differentiation remains especially controversial. Here, we show that tonic BCR signal strength influences PC commitment in vivo. Using immuno-globulin light chain transgenic mice expressing suboptimal surface BCR levels and latent membrane protein 2A knock-in animals with defined BCR-like signal strengths, we show that weak, antigen-independent constitutive BCR signaling facilitates spontaneous PC differentiation in vivo and in vitro in response to TLR agonists or CD40/IL-4. Conversely, increasing tonic signaling completely prevents this process that is rescued by lowering surface BCR expression or through the inhibition of Syk phosphorylation. These findings provide new insights into the role of basal BCR signaling in PC differentiation and point to the need to resolve a strong BCR signal in order to guarantee terminal differentiation.
authors.affiliation: Université de Limoges, CNRS UMR 7276, Limoges, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Lechouane
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonaud
authors.forename: Laurent
authors.initials: L
authors.lastname: Delpy
authors.forename: Stefano
authors.initials: S
authors.lastname: Casola
authors.forename: Zeliha
authors.initials: Z
authors.lastname: Oruc
authors.forename: Guillaume
authors.initials: G
authors.lastname: Chemin
authors.forename: Michel
authors.initials: M
authors.lastname: Cogné
authors.forename: Christophe
authors.initials: C
authors.lastname: Sirac
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D053668:Syndecan-1 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D011947:Receptors, Antigen, B-Cell; D053668:Syndecan-1; D051193:Toll-Like Receptors; D014763:Viral Matrix Proteins