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B-cell terminal differentiation into antibody secreting plasma cells (PCs) features a transcriptional shift driven by the activation of plasma cell lineage determinants such asBlimp-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 immunoglobulin 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.Keywords: B cells r BCR r LMP2A r Plasma cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSignaling emanating from the B-cell receptor (BCR) is necessary for B lymphocyte survival at all stages of differentiation [1][2][3][4][5]. Accumulating evidence indicates that basal BCR signaling controls the development of the three major subsets of mature B cells: B-1, follicular (FO), or marginal zone (MZ) B cells [4,6]. In addition, it is well known that upon increased BCR signaling in response to antigen (Ag) binding, in the presence of T-cell Correspondence: Dr. Christophe Sirac e-mail: christophe.sirac@unilim.fr help, B lymphocytes can induce a differentiation program leading either to terminally differentiated antibody-secreting plasma cells (PCs), or to memory B cells [7][8][9]. The concerted induction of essential transcription factors such as Blimp-1, Xpb-1, and Irf-4, together with silencing of Pax-5 and Bcl-6 expression is responsible for PC differentiation, whereas their access to particular survival niches will determine their life span [10]. However, little is known about the initial signals governing entry into the PC compartment rather than the memory B-cell pool. studies have highlighted a inhibition of mitogen-induced PC differentiation by BCR signaling alone or in combination with CD40 and/or IL-4 ligation [12][13][14][15][16]. This inhibition is often considered as a mechanism to prevent PC differentiation during the GC reaction to favor memory B-cell formation [17,18]. Another interpretation for BCR negative control of PC differentiation applies to the specific inhibition of B cells expressing a self-reactive BCR [14,15]. However, most studies have been performed in vitro and there is still no in vivo evidence for BCR-dependen...

Antibody affinity maturation relies on activation-induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM) of immunoglobulin (Ig) loci. Class switch recombination (CSR) can in parallel occur between AID-targeted, transcribed, spliced and repetitive switch (S) regions. AID thus initiates not only mutations but also double-strand breaks (DSBs). What governs the choice between those two outcomes remains uncertain. Here we explore whether insertion of transcribed intronic S regions in a locus (Igk) strongly recruiting AID is sufficient for efficient CSR. Although strongly targeted by AID and carrying internal deletions, the knocked-in S regions only undergo rare CSR-like events. This model confirms S regions as exquisite SHM targets, extending AID activity far from transcription initiation sites, and shows that such spliced and repetitive AID targets are not sufficient by themselves for CSR. Beyond transcription and AID recruitment, additional IgH elements are thus needed for CSR, restricting this hazardous gene remodelling to IgH loci.