Signalling crosstalk in B cells: managing worth and need - PubMed (original) (raw)

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Signalling crosstalk in B cells: managing worth and need

Michael P Cancro. Nat Rev Immunol. 2009 Sep.

Abstract

The B cell receptor (BCR) and the receptor for B cell-activating factor (BAFFR) have complementary roles in B cells: BCR signals provide a cell-intrinsic measure of suitability for negative or positive selection, whereas BAFFR responds to homeostatic demands based on a cell-extrinsic measure of the size of the mature B cell pool. Because continuous signals from both receptors are required for B cell survival, it is probable that there are mechanisms to integrate the selective and homeostatic signals from these receptors. In this Opinion article, I describe recent evidence to indicate that crosstalk between the downstream biochemical pathways of these receptors mediates this interdependence, such that BCR signals generate a limiting substrate for BAFFR signal propagation.

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Figures

Figure 1

Figure 1. B cell differentiation and selection are controlled by the specificity of the BCR and the availability of BAFF

a. After the expression of a complete B cell receptor (BCR), specificity-based selection of B cells occurs at the immature B cell stage and again after exit from the bone marrow during the transitional B cell stages in peripheral lymphoid tissues. Selective elimination of B cells at the immature stage (negative selection) results from high avidity BCR engagement by the selecting ligand. B cells that undergo sustained, intermediate avidity BCR interactions with antigen persist to the transitional stages but die before they reach the mature stages. Positive selection also occurs, so B cells that fail to reach a minimum BCR signalling threshold undergo apoptosis. B cells in which BCR signalling reaches the minimum threshold necessary for positive selection but does not reach the high threshold that would result in negative selection survive and enter the mature B cell pool. Expression of the receptor for B cell-activating factor (BAFFR) is first induced at the transitional stages of B cell development and increases as the cells mature. b. Signals delivered through BAFFR can modulate the stringency of positive selection of transitional B cells. When the mature B cell pool is full and free BAFF levels are low (left panel), transitional B cells compete for limited free BAFF, so BAFFR occupation on these cells is limited and the range of BCR signal strengths that can promote survival is narrow. When BAFF levels are high (for example, as a result of ‘space’ in the mature B cell pool) (right panel), the range of BCR signal strengths that can promote B cell survival is broader, because in the presence of excess BAFF, BAFFR signalling on transitional B cells is maximal.

Figure 2

Figure 2. Signalling crosstalk underlies the mutual dependence of the BCR and BAFFR in B cell development and survival

B cell receptor (BCR) signals are initiated by SRC family kinases such as LYN, which phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMs) on the BCR signalling complex (Igα and Igβ). Phosphorylation of SYK then initiates multiple interacting downstream pathways (for simplicity, not all pathways and components are shown). These include the phosphoinositide 3-kinase (PI3K) pathway, which culminates in the activation of AKT1 and nuclear factor of activated T cells (NFAT), and the activation of Bruton’s tyrosine kinase (BTK), which has multiple downstream effects. Among these effects are the induction of phospholipase Cγ2 (PLCγ2) activity, which mediates hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to produce inositol-1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG), and the activation of protein kinase Cβ (PKCβ), which in turn leads to activation of the canonical nuclear factor-κB1 (NF-κB1; also known as p50) pathway through the BCL-10–MALT1–CARMA1 complex. These mediators have multiple downstream effects, including the upregulation of p100 transcription but not p100 processing. By contrast, the B cell-activating factor receptor (BAFFR) preferentially activates the non-canonical NF-κB2 (also known as p52) pathway by inhibiting interactions between tumour necrosis factor receptor-associated factor 2 (TRAF2) and TRAF3 that otherwise would mediate the degradation of NF-κB-inducing kinase (NIK). The resulting NIK accumulation leads to increased processing of p100 and the generation of NF-κB2–ReLB heterodimers, which translocate to the nucleus where they upregulate the transcription of anti-apoptotic genes. However, BAFFR signals do not generate additional p100 and they can rapidly exhaust cellular stores of p100. So, only continued signalling through both receptors yields sustained anti-apoptotic gene expression and supports B cell survival. BCL-10, B cell lymphoma 10; BLNK, B cell linker; CARMA1, also known as CARD11 (caspase recruitment domain-containing protein 11); GRB2, growth factor receptor-bound protein 2; IKK, inhibitor of NF-κB kinase; MALT1, mucosa-associated lymphoid tissue lymphoma translocation gene 1; MCL1, myeloid cell leukaemia sequence 1.

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