Abstract
The major function of B lymphocytes is to sense antigens and to produce protective antibodies after activation. This function requires the expression of a B-cell antigen receptor (BCR), and evolutionary conserved mechanisms seem to exist that ensure that B cells without a BCR do not develop nor survive in the periphery. Here, we show that the loss of BCR expression on Burkitt lymphoma cells leads to decreased mitochondrial function and impaired metabolic flexibility. Strikingly, this phenotype does not result from the absence of a classical Syk-dependent BCR signal but rather from compromised ER expansion. We show that the reexpression of immunoglobulins (Ig) in the absence of the BCR signaling subunits Igα and Igβ rescues the observed metabolic defects. We demonstrate that immunoglobulin expression is needed to maintain ER homeostasis not only in lymphoma cells but also in resting B cells. Our study provides evidence that the expression of BCR components, which is sensed in the ER and shapes mitochondrial function, represents a novel mechanism of metabolic control in B cells.
Highlights
The primary role of the B-cell antigen receptor (BCR) on mature B cells is to recognize antigen and to initiate a signaling cascade resulting in cell activation and clonal selection
Consistent with previous reports showing that BCR ablation does not lead to cell death in cMyc-driven lymphoma (Varano et al, 2017; He et al, 2018), we did not observe any significant differences in cell viability and proliferation between BCR-KO and wild-type (WT) cells (Fig 1C)
To confirm our findings that lymphoma cells are able to adapt to the loss of the BCR, we studied another BCR-negative Burkitt lymphoma line, namely, DG75 with a defective membrane-bound Ig (mIg) H gene
Summary
The primary role of the BCR on mature B cells is to recognize antigen and to initiate a signaling cascade resulting in cell activation and clonal selection. Syk plays an essential role in signal initiation and amplification upon BCR engagement, and Syk-deficient B cells display severe functional defects and impaired survival (Turner et al, 1995; Klasener et al, 2014). In addition to playing a central role in B-cell activation, the BCR has been shown to support survival of naıve mature B cells. B cells that because of a defective H or Igα gene are BCR negative display a reduced survival, demonstrating the importance of the BCR in B cell maintenance (Lam et al, 1997; Kraus et al, 2004)
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