B lymphocyte homeostasis depends on tonic and induced BCR signaling and receptors sensitive to trophic factors, such as B cell-activating factor receptor (BAFF-R or BR3) during development and maintenance. This review will discuss growing evidence suggesting that the signaling mechanisms that maintain B cell survival and metabolic fitness during selection at transitional stages and survival after maturation rely on cross-talk between BCR and BR3 signaling. Recent findings have also begun to unravel the molecular mechanisms underlying this crosstalk. In this review I also propose a model for regulating the amplitude of BCR signaling by a signal amplification loop downstream of the BCR involving Btk and NF-κB that may facilitate BCR-dependent B cell survival as well as its functional coupling to BR3 for the growth and survival of B lymphocytes.

B cell receptor signaling guides the selection of immature B cells in the bone marrow. After exit from the bone marrow, these immature B cells go through additional checkpoints at early and late transitional stages in the spleen (1). Tonic as well as BCR-induced signals, together with B cell-activating factor (BAFF)3 receptor (BR3) signals, facilitate the production and maintenance of immunocompetent pools of mature follicular (Fo)BI and FoBII cells and marginal zone (MZ) B cells while remaining self-tolerant (2). Although the molecular mechanisms that implement developmental checkpoints during peripheral B cell development and survival remain poorly defined, new insights have emerged from the distinct ways B cells at different developmental stages respond to BCR and BR3 engagement. Recent evidence also suggests that Bruton’s tyrosine kinase (Btk) and the transcription factor NF-κB, particularly c-Rel, are central in the regulation of B cell survival through a BCR/Btk signaling axis that constitutes a positive autoregulatory loop to increase signal strength with B cell maturation (3, 4). This signaling axis also mediates crosstalk between BCR and BR3, which is emerging as a fundamentally important mechanism to regulate B cell survival. Although critical components and events downstream of the BCR are well known, the emerging mechanisms of BCR signaling through a positive feedback signaling loop and its role in the re-enforcement of BR3 function are subjects of intense research and will be discussed in this review.

The maturation process of early transitional (T1) into late transitional (T2) and mature B cells is hampered by the presence of self-reactive BCRs that were not selected against in the bone marrow. Clonotypes bearing these BCRs must either be silenced or eliminated. Thus, negative selection of self-reactive immature B cells likely operates at the T1 stage and can occur by multiple mechanisms, including deletion, anergy, or receptor editing upon Ag encounter (5, 6, 7). In vivo, strong BCR signals are proposed to drive these processes, whereas transition into a T2 B cell may occur through weak BCR engagements or in a ligand-independent fashion through tonic BCR signaling (8, 9, 10, 11). Analysis of the peripheral B cell repertoire, both in mice and humans, supports the model in which the formation of a mature B cell repertoire is also regulated by a positive selection checkpoint that likely occurs at later stages of transitional B cell development (5, 8, 9, 10, 11, 12, 13, 14). However, in lieu of an identified ligand or ligands, it remains possible that selection into a mature B cell pool is regulated by developmental stage-specific quantitative and qualitative alterations in BCR signaling. Thus, alterations in BCR signaling during T1 to T2 transition play a critical role in B cell maturation. A hypothesis is that the T1 cell clones that do not undergo apoptosis due to a strong BCR signal increase basal or tonic BCR signaling by a developmentally regulated default pathway. These T1 cells gradually increase the expression of BR3 and BCR coreceptors and perhaps intracellular signaling proteins. Thus, upon differentiation, T2 cells display enhanced expression of CD19, CD21, and BR3 (Ref. 15 and data not shown). This increases BCR signaling competence and BAFF-dependent survival potential of T2 relative to T1 B cells as was recently suggested (4). Regardless of the mechanism of selection, a failure to implement transitional B cell checkpoints is associated with human autoimmune diseases such as SLE, as reflected by a disproportionate increase in T1 cells in SLE patients (16, 17).

The cellular and molecular basis by which checkpoints during transitional to mature B cell development is implemented is the subject of intensive research. Based on currently available information, there are at least three subpopulations of transitional B cells; T1 (AA4+IgMhighIgDCD23), T2 (AA4+IgMhighIgDhighCD23+CD21int; where “int” is intermediate), and T2-preMZ (AA4+IgMhighIgDCD23+CD21high) (1, 13, 15, 18, 19, 20, 21) before their selection into mature Fo or MZ B cells (Fig. 1). According to this scheme, T1 B cells develop into T2 B cells, which in turn are thought to serve as the precursor to either subsequent transitional (T2-preMZ) or mature follicular (FoBI: IgMintIgDhighCD23+CD21int; FoBII: IgMhighIgDhighCD23+CD21int) B cells (4, 19, 20). The T2-preMZ cells likely give rise to MZ B cells (4, 19, 20).

FIGURE 1.

A model of peripheral B cell development. Immature B cells are generated from precursor B cells in the bone marrow. Upon surface expression of IgM (BCR), the immature B cells leave the bone marrow and emigrate to the spleen as T1 B cells. In the spleen, T1 B cells develop into T2 B cells, which in turn are thought to serve as the precursor to either subsequent transitional (T2-preMZ) or mature FoBI and FoBII B cells. The T2-preMZ cells likely give rise to MZ B cells. An analogous pathway of B cell maturation has been recently described to exist in the bone marrow (1920 ).

FIGURE 1.

A model of peripheral B cell development. Immature B cells are generated from precursor B cells in the bone marrow. Upon surface expression of IgM (BCR), the immature B cells leave the bone marrow and emigrate to the spleen as T1 B cells. In the spleen, T1 B cells develop into T2 B cells, which in turn are thought to serve as the precursor to either subsequent transitional (T2-preMZ) or mature FoBI and FoBII B cells. The T2-preMZ cells likely give rise to MZ B cells. An analogous pathway of B cell maturation has been recently described to exist in the bone marrow (1920 ).

Close modal

The distinct biological consequences in T1 and T2 B cells to BCR engagement do suggest differences in the nature of intracellular signaling, the downstream targets, or both in the two transitional B cell subpopulations (22, 23, 24). Consistently, recent investigations have shed some light on potential differences in the intracellular signaling responses within transitional B cell populations to BCR engagement. Furthermore, analyses of the B cells in genetic models of defective BCR signaling suggest stage-specific functions for some of the signaling components. However, the biochemical evidence of a stage-specific function for BCR signaling is largely lacking. Our proteomics analysis of biochemically enriched lipid rafts from T1 and T2 cells after BCR cross-linking did not reveal any major qualitative differences among the known signaling components (J. Llanes and W. N. Khan, unpublished results). Thus, quantitative differences in BCR signaling may determine distinct biological outcomes within the transitional B cell subpopulations. Conceptually, quantitative differences in the signaling programs can implement distinct thresholds or strengths of BCR signaling, which is considered to be the major mechanism of B cell fate decisions. Consistent with this, potential positive regulatory mechanisms gain strength in BCR signaling as T1 cells progress through T2 and mature B cell stages (discussed below).

Because of the significance of phosphoinositide metabolism in BCR signaling and control of B cell biological responses, others and we have investigated BCR induction of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG) lipid second messengers (LSMs) in immature or transitional B cell subsets (15, 25, 26, 27). We found that BCR stimulation in vitro induced the accumulation of DAG and IP3 in T2 and mature Fo B cells, but not in T1 or Btk-deficient B cells (15, 25, 26). However, the reduced accumulation of LSM metabolism in T1 relative to T2 B cells does not seem to affect the NF-κB signaling pathway, at least at early time points after BCR stimulation (28, 29, 30). Consistent with this hypothesis T1, T2, and mature B cell populations can activate IκB kinase (IKK) and induce degradation of IκBα, processes that require the activation of protein kinase C (PKC) β by DAG and Ca+2. In addition, NF-κB DNA binding is also comparable among T1, T2, and mature B cell populations at early time points (Refs. 28 and 31 and unpublished data). Despite NF-κB activation, genes encoding antiapoptotic A1 and Bcl-xL proteins are not induced in T1 but are induced in T2 and mature B cells, suggesting the existence of a T1 stage-specific gene suppression mechanism that selectively affects gene expression in response to BCR but not to TLR stimulation (28, 31).

The comparable activation of NF-κB in transitional and mature B cell subsets may be explained by the complex regulation of LSMs after their formation, which is differentially regulated in T1 vs more mature B cells. For example, despite reduced BCR-induced levels of IP3, T1 cells can however increase intracellular calcium concentration ([Ca2+]i) in response to BCR engagement (15, 32). This conflict could possibly be explained by the more rapid breakdown of DAG and the formation of higher order inositol phosphates from IP3 in T1 than in T2 and mature B cells by the rapid action of DAG kinases and IP3 kinases (15, 32, 33, 34, 35). Whether the transient levels of DAG and IP3 are responsible for activating NF-κB in response to BCR remains to be determined.

We recently described how, in addition to the classical NF-κB activation discussed above, a second phase of NF-κB activation occurs in B cells after long-term BCR stimulation via transcriptional activation of c-rel gene and c-Rel protein synthesis (28). This long-term c-Rel induction coincides with increased levels of antiapoptotic genes as well as up-regulation of BR3 and its substrate, p100 (NF-κB2), in T2 and mature B cells. Thus, in T2 and mature B cells two distinct NF-κB-dependent mechanisms control B cell survival; the initial activation of the classical NF-κB pathway followed by the long-term induction of c-Rel. The mechanisms that control c-Rel nuclear activity independently of the classical NF-κB pathway remain unknown. Together, these two phases of gene regulation provide sufficient levels of antiapoptotic proteins for extended periods for NF-κB to be effective as an antiapoptotic transcription factor. Consistently, the promoter regions of antiapoptotic genes associated with B cell survival, A1 and Bcl-xL, are direct targets of the c-Rel subunit of NF-κB. We propose that sustained induction of c-Rel in T2 and mature B cells is a critical regulator of differential survival of T1 and T2 B cells (28).

Btk and the transcription factor NF-κB are central in the regulation of B cell apoptosis (3, 4, 30, 36, 37, 38). Recent evidence suggests that Btk levels change with BCR stimulation, which may regulate the strength and extent of BCR signaling. Intracellular levels of Btk may play an important role in a quantitative increase in BCR signaling with B cell maturation. Nisitani et al. showed that Btk protein levels in splenic B cells are maximally increased (7- to 10-fold) within 4 h of BCR stimulation by a posttranscriptional mechanism involving Btk and PI3K (39). This up-regulation also occurs in vivo after T cell-dependent or T cell-independent immunization. The in vivo studies suggested that, in addition to BCR signaling, Btk induction also involves other receptors in B cells. Furthermore, NF-κB activation contributes to Btk gene transcription, suggesting that the BCR/Btk signaling axis constitutes a positive autoregulatory loop (40). Because genetic evidence indicates that B cell dependence on NF-κB increases with maturation, it stands to reason that BCR signaling via Btk would lead to an increase in intracellular levels of Btk and increased activation of its signaling pathways, including NF-κB. If this is true, the Btk-NF-κB positive feedback loop could lead to maturation of the BCR signaling apparatus and a quantitative increase in BCR signaling potential as transitional B cells develop into mature B cells. This is significant because Btk dosage is a genetically defined parameter in mediating BCR function, and Btk levels are rate limiting in the transmission of certain BCR signal transduction pathways, including c-Rel induction (28, 41). Indeed, the ability to activate NF-κB in a sustained manner, particularly the c-Rel NF-κB subunit, increases with B cell maturation (28). In contrast to T1 cells, BCR-induced c-Rel signaling in T2 and mature B cells regulates the expression and function of BR3, enhancing and reinforcing prosurvival signaling under BR3 control (28, 42, 43).

It is notable that NF-κB-responsive antiapoptotic genes, including Bcl-xL and A1, which are induced in T2 and mature Fo B cells are directly controlled by the c-Rel subunit of NF-κB (44, 45, 46). A critical role for c-Rel in B cell survival was also documented in experiments silencing the c-Rel gene in tumor B cell lines (47). Thus, we investigated the possibility that T1 B cells may be unable to activate c-Rel to the extent and/or duration necessary to induce an antiapoptotic program and, thus, render them sensitive to BCR-induced apoptosis. This model would also predict that apoptosis-resistant T2 and mature B cells are capable of long-term c-Rel response. Consistent with this model, BCR signaling in mature B cells induced long-term nuclear expression of c-Rel, which coincided with the stable expression of antiapoptotic genes. A similar c-Rel response was also observed in T2 and mature Fo B cells in response to BCR stimulation, whereas T1 cells failed to do so (28). This long-term c-Rel expression required de novo c-Rel synthesis in a Btk-dependent manner. Like Btk-deficient B cells, T1 cells also failed to up-regulate sustained c-Rel expression, whereas sustained c-Rel expression was evident in T2 cells (28). A requirement for Btk, and by inference DAG and IP3, in BCR-induced de novo c-Rel synthesis suggests the involvement of NF-AT and NF-κB in c-Rel gene transcription. Binding sites for both transcription factors have been identified in the c-Rel promoter; however, it is controversial as to which sites contribute to constitutive vs Ag receptor-induced c-Rel gene expression (48, 49). Because basal c-Rel expression is regulated by PI3K, the BCR/PI3K pathway likely forms a BCR signaling module that regulates resting B cell survival, whereas Btk regulates the expression of c-Rel in response to active BCR signaling (28, 50). Thus, the BCR/Btk signaling module would be more relevant in BCR-induced B cell survival, which may include positive selection of T2 cells and activation of mature B cells. We propose that the ability to sustain nuclear c-Rel by the two BCR signaling modules is of paramount importance in the apoptotic vs survival response of B cells at the resting state and to BCR engagement.

It is clear from the above discussion that BCR signaling differentially controls survival in T1 and T2 cells and thus regulates the entrance of select B cell clones into the mature B cell compartment based on BCR specificities and/or stage-specific alterations in the strength of BCR signaling (5, 10, 13, 14). Evidence suggests that trophic or environmental signals influence these outcomes significantly, and inappropriate effects may lead to the development of autoimmune diseases (51, 52, 53). BAFF, also known as TNFSF13B, BLys, TALL-1, THANK, or zTNF4, is the most critical of these trophic factors affecting the regulation of B cell maturation and the subsequent maintenance of mature B cells (2, 54). Discovery of the BAFF/BR3 system has reshaped our thinking of how the size of the B lymphocyte compartment is managed. BAFF-transgenic mice have greatly increased numbers of peripheral B cells as well as serum Abs. With age, they develop SLE-like autoimmune disease (55, 56, 57). Consistent with this, overproduction of BAFF has been shown to be associated with human autoimmune diseases and B cell malignancies. Emerging evidence suggests that BR3 is as critical for B cell survival as the BCR, and that BCR and BR3 are functionally linked in the regulation of B cell survival (28, 43, 54).

Three TNF receptors are known to bind BAFF: the B cell maturation Ag (BCMA), a transmembrane activator and calcium-modulating/cyclophilin ligand-interacting protein (TACI), and BR3 (54). BR3 and TACI are expressed on all B cell subsets (lowest level on T1 B cells, highest levels on T2 and MZ B cells), whereas BCMA is expressed primarily on plasma cells and, hence, is dispensable for the development of primary B cell repertoire (58). Targeted gene deletion of BR3 profoundly reduces the numbers of transitional as well as mature B cells in the spleen; however, all subpopulations are detected (59, 60). A naturally occurring mutation (A/WySnJ) in the BR3 cytoplasmic tail results in a similar B cell deficiency (61, 62). Consistent with this, treatment of BR3-deficient mice with BAFF does not increase mature splenic B cells (58). In contrast, mice deficient for TACI have increased splenic B cells and serum Igs, which was suggested to mean a potential negative regulatory role for TACI in B cell survival (63). However, a simpler explanation might be that the lack of TACI allows more circulating BAFF to become available, which can bind to BR3 and increase B cell numbers.

Recent reports demonstrate that BCR regulates the expression of BR3 (42). Thus, BCR may also control B cell survival and sensitivity to environmental cues indirectly via this prosurvival receptor (28, 43, 54). Others and we have examined how BCR signaling influences BR3 expression and function. We found that BCR-induced expression of BR3 requires Btk and sustained c-Rel activation. Thus, Btk and c-Rel are not only important in the regulation of B cell survival directly by inducing the expression of antiapoptotic genes but also indirectly via increasing the expression and function of BR3 (28, 43). It is interesting to note that Btk-deficient mice (Fig. 2 A) have a specific deficiency of FoBI cells, presumably due to its active role in the positive selection, whereas MZ B cells are present. One interpretation is that, in the absence of Btk, BCR generates weaker signals that favor the development of MZ B cells (19, 20). The other but not mutually exclusive possibility is that circulating BAFF is increased due to reduced Fo BI cells in Btk-deficient mice. The increased BAFF may support MZ B cell survival in this relatively B lymphopenic environment. Consistent with this idea, preferential expansion of MZ B cells has been observed in other lymphopenic mice.

FIGURE 2.

Schematic of BCR signal amplification and BCR reinforcement of BR3 survival signaling. A, BCR signaling leads to activation of the classical NF-κB pathway via Btk-dependent mechanisms. BCR signaling increases the levels of Btk protein via posttranscriptional as well as NF-κB-mediated transcriptional up-regulation of the gene encoding Btk (40 ). In this model, successive increases of Btk and the NF-κB positive autoregulatory loop would lead to a quantitative increase in the BCR signaling potential in T2 and mature B cells that do not undergo rapid apoptosis. Additionally, enhanced and stable BCR signaling produces long-term nuclear expression of c-Rel and its target antiapoptotic genes (e.g., A1 and Bcl-xL) promote B cell survival. The sustained c-Rel response also results in expression of BR3 and its substrate, p100, enhancing and re-enforcing BR3 survival signaling through activation of the alternative NF-κB pathway. B, BAFF engagement with BR3 also activates the classical NF-κB pathway via a Btk-dependent mechanism, resulting in an increase in BR3 and p100 (67 ). This affords BR3 with self-sufficiency in an autoregulatory feedback mechanism for low-level sustained activation of both NF-κB pathways, further strengthening BR3-mediated B cell survival.

FIGURE 2.

Schematic of BCR signal amplification and BCR reinforcement of BR3 survival signaling. A, BCR signaling leads to activation of the classical NF-κB pathway via Btk-dependent mechanisms. BCR signaling increases the levels of Btk protein via posttranscriptional as well as NF-κB-mediated transcriptional up-regulation of the gene encoding Btk (40 ). In this model, successive increases of Btk and the NF-κB positive autoregulatory loop would lead to a quantitative increase in the BCR signaling potential in T2 and mature B cells that do not undergo rapid apoptosis. Additionally, enhanced and stable BCR signaling produces long-term nuclear expression of c-Rel and its target antiapoptotic genes (e.g., A1 and Bcl-xL) promote B cell survival. The sustained c-Rel response also results in expression of BR3 and its substrate, p100, enhancing and re-enforcing BR3 survival signaling through activation of the alternative NF-κB pathway. B, BAFF engagement with BR3 also activates the classical NF-κB pathway via a Btk-dependent mechanism, resulting in an increase in BR3 and p100 (67 ). This affords BR3 with self-sufficiency in an autoregulatory feedback mechanism for low-level sustained activation of both NF-κB pathways, further strengthening BR3-mediated B cell survival.

Close modal

Like BCR, BR3 is also biochemically linked to NF-κB (64, 65). However, unlike BCR, BR3 has been shown to activate both the classical and alternative NF-κB pathways (Fig. 2,B). Among the three BAFF receptors, only BR3 activates the alternative NF-κB pathway. Also, the alternative pathway is more robustly activated than the classical NF-κB pathway by BR3 signaling (64, 66, 67). The activation of the alternative NF-κB pathway involves NF-κB-inducing kinase and activation of IKKα, which phosphorylates p100 and leads to its processing into p52 (64, 65). The observation that primary B cells lacking p50 or p52 (Fig. 2) display defective in vitro survival in the presence of soluble BAFF suggests that NF-κB is at least partially responsible for BAFF-mediated B cell survival and that both the classical and alternative pathways are involved in this process (64, 66, 67, 68). Recently a novel mode of NF-κB-dependent gene expression by BR3 was discovered. In this unexpected mechanism, BR3 associates with IKKβ/c-Rel and histone H3 in the nucleus where IKKβ phosphorylates histone H3 and regulates gene expression (69).

What is the significance of activating multiple NF-κB pathways? A hypothesis would be that the quantity and quality of the specific NF-κB DNA binding subunits that translocate to the nucleus and activate genes may be critically important in determining the distinct biological outcomes in different transitional and mature B cell populations. Because BCR signaling is at the center of all B cell selection processes, the regulation and extent of BCR signaling to NF-κB (and other signaling pathways) in B cells undergoing negative selection, positive selection, or maintenance must be clearly different and may influence NF-κB subunit composition and the extent of DNA binding to distinct target genes, including BR3. This delicate regulation combined with BR3-mediated activation of primarily the alternative NF-κB pathway may produce specific responses in distinct B cell populations.

Yet another mechanism that promotes the intersection of BCR with BR3 signaling and strengthens their functional coupling is BCR regulation of the BR3 substrate, p100 (Fig. 2). BAFF interaction with BR3 activates the alternative NF-κB pathway, which involves IKKα-mediated phosphorylation and the subsequent proteolytic processing of p100 (NF-κB2) to p52, which preferentially dimerizes with RelB, and p52/RelB translocate to the nucleus (64, 65). Because proteolysis is an irreversible process, conversion to p52 results in the elimination of the precursor protein p100; therefore, sustained activation of the alternative pathway must require continuous production of p100. Consistent with this model, recent studies show that BCR tonic and induced signaling produces de novo synthesis of p100 (28, 43). p100 is regulated at the transcriptional level via Btk- and c-Rel-dependent mechanisms (28). These results suggest that one mechanism for providing a p100 supply for the sustained activation of the alternative NF-κB pathway involves BCR signaling through the classical NF-κB pathway and c-Rel (28). Indeed, loss of p50 results in a decrease in BCR-induced expression of BR3 as well as p100 (67).

In addition to the significance of concomitant BCR and BR3 signaling in B cell development, independent contribution of these receptors is evident by genetic studies with mice partially defective in both BCR (btk−/−) and BR3 (A/WySnJ) signaling; they display a complete block at the T1 stage with the absence of all peripheral B cells (K. L. Hoek, G. Carlesso, and W. N. Khan, manuscript in preparation). The functional link between BCR and BR3 also has ramifications for the development of B cell pathologies, including autoimmunity and the survival of B cell lymphomas. This suggests that when BCR signaling is perturbed, deregulation would influence BR3 expression and function and, thus, inappropriate B cell survival. Because TLRs are potent activators of the classical NF-κB pathway, they also induce the expression of BR3 and its downstream substrate, p100 (G. Carlesso, K. L. Hoek, and W. N. Khan, unpublished data), thus facilitating activation of the alternative NF-κB pathway by BR3. This regulation of BR3 expression and function raises the possibility that TLR engagement in B cells in an inappropriate context may lead to the development of autoimmune conditions, breakdown in B cell tolerance, or development of B cell lymphomas.

In addition to receiving re-enforcement from the BCR-induced expression of p100, BR3 is also self-sufficient in maintaining the signaling loop between classical and alternative NF-κB pathways (66, 67). Several observations are consistent with this possibility. First, BR3 is also capable of activating the classical NF-κB pathway in a Btk- and phospholipase C-γ2-dependent manner and proceeds via the phosphorylation of IKKβ and degradation of IκBα (67, 70). Furthermore, BR3 engagement with BAFF up-regulated transcriptional activation of the genes encoding BR3, as well as p100 and RelB. Unlike BCR, however, BR3 required p50/RelA heterodimers but did not require c-Rel for these processes. Although the survival of resting mature B cells is dependent on BCR signaling, these findings suggest that BR3 has the potential to maintain long-term activity of the alternative NF-κB pathway through activation of the classical NF-κB pathway. This model is consistent with the findings that Btk- or p50-deficient B cells survive poorly relative to wild-type controls in in vitro cultures containing BAFF (66, 67).

Although this review is focused on the NF-κB aspect of BR3 signaling, several other mechanisms of BR3-mediated B cell survival have been described that are independent of NF-κB transcriptional activity (Fig. 3;71). These include down-regulation of the proapoptotic molecule Bim and up-regulation of Mcl-1 via the ERK and Akt pathways, which are activated by a novel IKKα function (72, 73, 74). BAFF-induced activation of Akt/mTOR and Pim-2 signaling pathways are essential for the regulation of B cell growth and overall metabolic fitness (75). Akt is activated by PKCβ and phosphoinositide-dependent kinase-1 targeting of Ser473 and Thr308 downstream of PI3K in response to BAFF (74, 75). The implications of the levels of BR3 discussed in this review should be applicable to the NF-κB-independent mechanisms as well.

FIGURE 3.

Schematic of BAFF receptor (BR3) survival signaling. Interaction of BR3 with BAFF leads to activation of the PI3K/Akt, ERK, and Pim-2 signaling pathways via IKKα, apparently via mechanisms independent of transcriptional activity of the NF-κB pathway. Phosphoinositide-dependent kinase-1 (PDK1) and PKCβ are also implicated in Akt activation in response to BAFF (54 ). Following activation, Akt targets the phosphorylation and cytoplasmic sequestration of the Forkhead transcription factor FOXO3a, which, when in the nucleus, targets the expression of the proapoptotic gene Bim. ERK activity further reduces cellular levels of the Bim protein by phosphorylation and degradation. Concomitantly, Akt induces transcriptional induction of the antiapoptotic gene Mcl-1 and blocks the inhibition of protein translation by 4E-BP1, including that of the Mcl-1 protein. Akt/mammalian target of rapamycin (mTOR) and Pim-2 signaling implements this inhibition of 4E-BP1 in response to BAFF. In addition to skewing the balance toward prevalence of antiapoptotic proteins, Akt plays a critical role in cellular growth and anabolism via the rapamycin-sensitive mTOR pathway. Another mechanism through which BAFF interaction with BR3 prevents cell death is by blocking the entry of proapoptotic PKCδ to the nucleus. Thus, BAFF regulates B cell survival and growth by preventing apoptosis at multiple levels and by mobilizing a major cellular metabolic pathway involving mTOR under Akt control (71 ).

FIGURE 3.

Schematic of BAFF receptor (BR3) survival signaling. Interaction of BR3 with BAFF leads to activation of the PI3K/Akt, ERK, and Pim-2 signaling pathways via IKKα, apparently via mechanisms independent of transcriptional activity of the NF-κB pathway. Phosphoinositide-dependent kinase-1 (PDK1) and PKCβ are also implicated in Akt activation in response to BAFF (54 ). Following activation, Akt targets the phosphorylation and cytoplasmic sequestration of the Forkhead transcription factor FOXO3a, which, when in the nucleus, targets the expression of the proapoptotic gene Bim. ERK activity further reduces cellular levels of the Bim protein by phosphorylation and degradation. Concomitantly, Akt induces transcriptional induction of the antiapoptotic gene Mcl-1 and blocks the inhibition of protein translation by 4E-BP1, including that of the Mcl-1 protein. Akt/mammalian target of rapamycin (mTOR) and Pim-2 signaling implements this inhibition of 4E-BP1 in response to BAFF. In addition to skewing the balance toward prevalence of antiapoptotic proteins, Akt plays a critical role in cellular growth and anabolism via the rapamycin-sensitive mTOR pathway. Another mechanism through which BAFF interaction with BR3 prevents cell death is by blocking the entry of proapoptotic PKCδ to the nucleus. Thus, BAFF regulates B cell survival and growth by preventing apoptosis at multiple levels and by mobilizing a major cellular metabolic pathway involving mTOR under Akt control (71 ).

Close modal

The rules that govern B cell responses to BCR and BR3 signaling are context dependent with the stage of B cell development. Multiple outcomes, including apoptosis, survival, growth, differentiation, and proliferation in B cells, take place following engagement of these receptors. Although mechanisms regulating signal transduction pathways downstream of BCR have been elucidated, the mechanisms of BR3 signaling as well as the mechanisms of integrated BCR and BR3 signaling are currently the focus of intensive research. The current understanding is that T1 cells in the spleen die upon BCR engagement due to a failure to activate transcription factors or transcription of antiapoptotic genes. Potential positive selection of T2 cells is regulated by gain of resistance to BCR-induced apoptosis. This change from T1 to T2 cells is accompanied by an ability to induce sustained activation of c-Rel and the stable expression of antiapoptotic genes. This mode of c-Rel activation also endows T2 cells with the ability to grow and survive in response to BAFF by regulating the expression of BR3 and its substrate p100 and hence, re-enforcing the long-term activation of the alternative NF-κB pathway. These survival characteristics are retained after maturation in Fo B cells. However, in the resting state PI3K-mediated c-Rel expression may regulate B cell survival. Thus, therapeutic intervention of the positive signal amplification loop in BCR-induced Btk expression, its positive consequences on c-Rel activation, and BCR re-enforcement of the growth and survival function of BR3 may provide potential therapeutic targets in the treatment of autoimmune diseases and B cell lymphomas.

I thank Dr. Emily S. Clark for careful reading of the manuscript and helpful discussions and Jacqueline A. Wright for helpful discussions.

The authors have no financial conflict of interest.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1

This work was supported in part by National Institutes of Health AI060729 (to W.N.K.).

3

Abbreviations used in this paper: BAFF, B cell-activating factor; BR3, BAFF receptor; Btk, Bruton’s tyrosine kinase; DAG, diacylglycerol; Fo, follicular; int, intermediate; IKK, IκB kinase; IP3, inositol-1,4,5-triphosphate; LSM, lipid second messenger; MZ, marginal zone; PKC, protein kinase C; SLE, systemic lupus erythematosus; T1, early transitional type 1 (B cell); T2, late transitional type 2 (B cell); TACI, transmembrane activator and calcium-modulating/cyclophilin ligand-interacting protein.

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