Regulation of B-cell entry into the cell cycle

Abstract

B cells are induced to enter the cell cycle by stimuli including ligation of the B-cell receptor (BCR) complex and Toll-like receptor (TLR) agonists. This review discusses the contribution of several molecules, which act at distinct steps in B-cell activation. The adapter molecule Bam32 (B-lymphocyte adapter of 32 kDa) helps promote BCR-induced cell cycle entry, while the secondary messenger superoxide has the opposite effect. Bam32 and superoxide may fine tune BCR-induced activation by competing for the same limited resources, namely Rac1 and the plasma membrane phospholipid PI(3,4)P(2). The co-receptor CD22 can inhibit BCR-induced proliferation by binding to novel CD22 ligands. Finally, regulators of B-cell survival and death also play roles in B-cell transit through the cell cycle. Caspase 6 negatively regulates CD40- and TLR-dependent G(1) entry, while acting later in the cell cycle to promote S-phase entry. Caspase 6 deficiency predisposes B cells to differentiate rather than proliferate after stimulation. Bim, a pro-apoptotic Bcl-2 family member, exerts a positive regulatory effect on cell cycle entry, which is opposed by Bcl-2. New insights into what regulates B-cell transit through the cell cycle may lead to thoughtful design of highly selective drugs that target pathogenic B cells.

Fig. 1. Signaling elements that modulate B-cell entry into the cell cycle

B lymphocytes receive mitogenic signals through receptors such as the BCR or TLRs. Proximally, adapter proteins like Bam32 and components of the NADPH oxidase complex (Nox) can function to positively or negatively modulate BCR signaling. BCR signals are also modulated by CD22 or CD19 coreceptors associating with the BCR. Finally, downstream regulators, including caspases and Bcl-2 family members such as Bim, influence the rate of B-cell entry into the cell cycle.

Fig. 2. Competition between Bam32 and the NADPH oxidase complex in B cells

Ag triggering of the BCR initiates activation of PTKs Syk and Lyn. Syk activates the PI3K pathway, responsible for catalyzing the formation of PIP₃. Bam32 and p47^phox are recruited to the cell surface when the SHOP phosphatase converts PIP3 to PI(3,4)P2. Lyn phosphorylates Y139 on Bam32, a key step in Bam32's ability to modulate downstream pathways. Bam32 and the NADPH oxidase compete not only for access to a limited pool of inositol lipids but also for a limited pool of the small GTPase Rac. Retardation of Bam32 KOI B-cell entry into the cell cycle may be due in part to enhanced BCR-induced superoxide generation.

Fig. 3. Cis and trans CD22–CD22L interactions send qualitatively different signals to B cells

(A) Cis CD22–CD22L interactions attenuate BCR signaling so the thresholds required for Ag-induced B-cell activation and for MZ of FO B-cell development are shifted. (B) Trans interactions between B-cell CD22 and DC–CD22L on the DC disrupts complex formation and allows CD22 signaling to promote survival and block B-cell entry into the cell cycle. The nature of DC–CD22L shown in orange is not known.

Fig. 4. Regulation of B-cell entry into G₁ by Caspase-6

Casp6 cleaves and inactivates substrates, which inhibit B cells from progressing from G0 into G1 after mitogenic stimulation. Casp6 may also target as a substrate, Rb, which suppresses S phase entry. In Caps6 KO B cells, elevated levels of Rb protein inhibit proliferation, even though more Casp6 KO B cells enter G1. Instead, differentiation into plasma cells and Ig production are increased.