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

tails of these molecules, and in particular their ITAM motifs are crucial for B cell development (Kraus et al., Harvard Medical School 200 Longwood Avenue 2001; Reichlin et al., 2001; Torres et al., 1996), and that the signals transduced through the Ig␣/Ig␤ heterodimer Boston, Massachusetts 02115 2 Institute for Genetics are involved in both positive and negative selection of the developing B cells (Kraus et al., 1999; Torres and University of Cologne Weyertal 121 Hafen, 1999). The notion of a checkpoint in B cell development D-50931 Cologne Germany marked by BCR expression was based on gene targeting experiments in which components of the BCR were inac-3 New York University Department of Biology tivated by germline mutations (Rajewsky, 1996) or Ig␤ was downregulated at the immature B cell stage (Meffre 1009 Main Building 100 Washington Square East and Nussenzweig, 2002). However, a subsequent experiment resulting in the ablation of the BCR in mature B New York, New York 10003 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 interferon, 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