Survival of Resting Mature B Lymphocytes Depends on BCR Signaling via the Igα/β Heterodimer

cells suggested that rather than marking a developmental checkpoint, the dependence of B cell maintenance on BCR expression is a characteristic feature of Summary B cell physiology from the stage of immature B cell generation in fetal liver or bone marrow (BM) to that of We previously showed that type I interferon-induced, Cre-mediated ablation of surface BCR expression in the mature, long-lived B cell populating the peripheral B cell compartment (Lam et al., 1997). mature B cells through Ig-heavy chain deletion results in apoptosis of these cells. This led to the hypothesis Although other work indirectly supports this view (Fuentes-Panana et al. 2004), the above interpretation that survival signals from the BCR are vital for mature B cells. Here, we test two critical assumptions of this of the Lam et al. experiment remained speculative for two reasons. While it was evident that BCR ablation on model. First, we demonstrate loss of mature B cells upon induced mutation of a signaling module of the mature B cells led to apoptotic cell death, it remained to be established that this was due to the loss of BCR BCR, not precluding BCR surface expression. Second, we show that the cells are also lost upon BCR inactiva-signaling. Clearly, other interpretations are possible, such as the BCR serving as a scaffold for another signal-tion in the absence of an exogenous inducer like inter-feron, excluding that cell death depends on previous ing structure or, in a more trivial way, that loss of BCR surface expression leads to cell death because of im-cellular activation by the latter. Kinetic data demonstrate that BCR-less mature B cells have a severely proper processing of its components in the endoplasmic reticulum (Harding et al., 2002; Allison et al., 1991). An-reduced lifespan, with a half-life of 3–6 days. Together these results establish that BCR signaling is required other problem with the interpretation of the Lam et al. experiment is that type I interferon (IFN) was used for to keep resting mature B cells alive in vivo. the induction of Cre-mediated BCR ablation. As IFN is known to be a potent, albeit transient B cell activator Introduction (Braun et al., 2002), the loss of B cells upon IFN-induced BCR ablation could rely on previous activation of the The B cell antigen receptor (BCR) consists of membrane bound immunoglobulin (Ig) and the signal-transducing cells, akin to activation-induced cell death in T cells (Krueger et …