Generation of peripheral B cells occurs via two spatially and temporally distinct pathways

Lindsley, R. Coleman; Thomas, Matthew; Bhaskar, Suryanarayanan; Allman, David

doi:10.1182/blood-2006-04-018085

Cited by 81 publications

(104 citation statements)

References 48 publications

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“…5 and Table S1). This mutation frequency is much lower (at least ninefold) than that in PP GC B cells (Table S1); we note, however, that, unlike GC B cells (36,37), immature/T1 B cells are only briefly exposed to AID activity and do not divide (38,39). Although the V H mutation frequency is extraordinary in 3H9 +/+ GC B cells, these cells (and their progeny) accumulate mutations over relatively long time periods-certainly weeks-punctuated by rounds of mutation, selection, and proliferation (37,40).…”

Section: Discussionmentioning

confidence: 92%

Activation-induced cytidine deaminase mediates central tolerance in B cells

Kuraoka

Holl

Liao

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

102

123

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The Aicda gene product, activation-induced cytidine deaminase (AID), initiates somatic hypermutation, class-switch recombination, and gene conversion of Ig genes by the deamination of deoxycytidine, followed by error-prone mismatch-or base-excision DNA repair. These processes are crucial for the generation of genetically diverse, high affinity antibody and robust humoral immunity, but exact significant genetic damage and promote cell death. In mice, physiologically significant AID expression was thought to be restricted to antigen-activated, mature B cells in germinal centers. We now demonstrate that low levels of AID in bone marrow immature and transitional B cells suppress the development of autoreactivity. Aicda −/− mice exhibit significantly increased serum autoantibody and reduced capacity to purge autoreactive immature and transitional B cells. In vitro, AID deficient immature/transitional B cells are significantly more resistant to anti-IgM-induced apoptosis than their normal counterparts. Thus, early AID expression plays a fundamental and unanticipated role in purging selfreactive immature and transitional B cells during their maturation in the bone marrow.Aicda-knockout mice | B-cell development | B-cell tolerance | competitive hematopoietic reconstitution | lymphopoiesis

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Section: Discussionmentioning

confidence: 92%

Activation-induced cytidine deaminase mediates central tolerance in B cells

Kuraoka

Holl

Liao

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

102

123

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“…The activation of canonical NF-κB signaling downstream of the BCR and/or BAFFR could be mediated by Bruton's tyrosine kinase (Btk) (5,25). Indeed, similar to the behavior of follicular B cells in the absence of canonical NF-κB signals, ectopic expression of Bcl2 rescues the generation of follicular B cells in x-linked immunodeficiency (xid) mice, which bear a mutation in Btk, and CD23 + transitional and follicular xid B cells are outcompeted by WT B cells (26,27).…”

Section: Discussionmentioning

confidence: 99%

Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells

Derudder

Herzog

Labi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Although canonical NF-κB signaling is crucial to generate a normal mature B-cell compartment, its role in the persistence of resting mature B cells is controversial. To resolve this conflict, we ablated NF-κB essential modulator (NEMO) and IκB kinase 2 (IKK2), two essential mediators of the canonical pathway, either early on in B-cell development or specifically in mature B cells. Early ablation severely inhibited the generation of all mature B-cell subsets, but follicular B-cell numbers could be largely rescued by ectopic expression of B-cell lymphoma 2 (Bcl2), despite a persisting block at the transitional stage. Marginal zone (MZ) B and B1 cells were not rescued, indicating a possible role of canonical NF-κB signals beyond the control of cell survival in these subsets. When canonical NF-κB signaling was ablated specifically in mature B cells, the differentiation and/or persistence of MZ B cells was still abrogated, but follicular B-cell numbers were only mildly affected. However, the mutant cells exhibited increased turnover as well as functional deficiencies upon activation, suggesting that canonical NF-κB signals contribute to their long-term persistence and functional fitness. Numerous stimuli activate the NF-κB signaling pathways in mature B cells. In mammals, the NF-κB family of transcription factors comprises five members (RelA, RelB, c-Rel, NF-κB1, and NF-κB2) whose activation is initiated by two major signaling pathways (5). The canonical pathway depends on the IκB kinase (IKK) complex, consisting of the structural protein NF-κB essential modulator (NEMO) and the IκB kinases IKK1 and IKK2. This complex triggers the degradation of a specific set of inhibitors of NF-κB and the induction of dimers containing RelA and/or c-Rel. The canonical pathway regulates NF-κB activation downstream of the BCR (5). The stimulation of the alternative pathway, mediated by NF-κB-inducing kinase and IKK1, leads to the partial proteolysis of the inhibitory precursor NF-κB2 and the activation of dimers containing RelB and/or the processed form of NF-κB2 through another set of receptors, including BAFFR (4).There is abundant evidence for a critical role of the canonical pathway in the generation and/or maintenance of mature B cells. The ablation of NEMO or IKK2 in the B-cell lineage, as well as conditional replacement of the latter by a kinase-dead IKK2, impaired the generation of the three mature B subsets and transitional 2 (T2) cells, a developmental stage preceding the mature stage (6-9). In the case of the kinase-dead IKK2, some mutant cells made it into the mature compartment but were completely outcompeted by WT cells over a period of 4 wk, upon blockade of B-cell generation in the bone marrow (6). Mechanistically, tonic BCR signaling could increase the production of NF-κB2 via canonical NF-κB activation in T2 and follicular B cells, sensitizing B cells to the prosurvival effect of BAFFR (10).However, other work suggested that canonical signals downstream of the BCR may not be critical for the maintenance of mature fo...

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“…+ transitional B cells generated in the presence of either BAFF or LPS corresponded phenotypically to a more advanced maturation state, with higher expression of CD21 and IgD and lower CD93, resembling the CD23 + fraction E subset in the BM (27) or its splenic counterpart, the transitional T2 subset (3)(4)(5). These results indicate that the expression of CD23 + molecule in maturing B cells promoted by LPS, similarly to BAFF, is not due to a simple isolated induction of CD23 expression but to the stimulation of a coherent set of phenotypic maturational changes on B lymphocytes.…”

Section: Lps and Baff Induce Similar Alterations In Surface Markers Amentioning

confidence: 99%

“…+ Fraction E stage and that CD23 neg stage is still poorly responsive to this stimulus (27 + B cells differentiated in the presence of LPS and BAFF in vitro, measuring in vitro proliferation upon stimulation with anti-CD40 plus IL-4 (Fig. 3A).…”

Section: Lps and Baff Induce Similar Alterations In Surface Markers Amentioning

confidence: 99%

TLR4 Promotes B Cell Maturation: Independence and Cooperation with B Lymphocyte-Activating Factor

Hayashi

Granato

Paiva

et al. 2010

The Journal of Immunology

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We have previously shown that TLR4 triggering promotes the generation of CD23+CD93+ transitional T2-like cells in vitro from mouse B cell precursors, suggesting a possible role for this receptor in B cell maturation. In this study, we perform an extensive study of cell surface markers and functional properties of B cells matured in vitro with LPS, comparatively with the well-known B cell maturation factor B lymphocyte-activating factor (BAFF). LPS increased generation of CD23+ transitional B cells in a TLR4-dependent way, upregulating IgD and CD21 and downregulating CD93, without inducing cell proliferation, in a manner essentially equivalent to BAFF. For both BAFF and LPS, functional maturation of the IgM+CD23+CD93+ cells was confirmed by their higher proliferative response to anti-CD40 plus IL-4 compared with IgM+CD23negCD93+ cells. BAFF-R-Fc–mediated neutralization experiments showed that TLR4-induced B cell maturation was independent of BAFF. Distinct from BAFF, maturation by LPS relied on the activation of canonical NF-κB pathway, and the two factors together had complementary effects, leading to higher numbers of IgM+CD23+CD93+ cells with their simultaneous addition. Importantly, BCR cross-linking abrogated the generation of CD23+ B cells by LPS or BAFF, indicating that signals mimicking central tolerance act on both systems. Addition of cyclosporin A reverted BCR-mediated inhibition, both for BAFF and LPS, suggesting similar regulation of signaling pathways by calcineurin. Finally, LPS-injected mice showed a rapid increase of mature B cells in the bone marrow, suggesting that TLR4 signaling may effectively stimulate B cell maturation in vivo, acting as an accessory stimulus in B cell development, complementary to the BAFF physiological pathway.

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Generation of peripheral B cells occurs via two spatially and temporally distinct pathways

Cited by 81 publications

References 48 publications

Activation-induced cytidine deaminase mediates central tolerance in B cells

Activation-induced cytidine deaminase mediates central tolerance in B cells

Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells

TLR4 Promotes B Cell Maturation: Independence and Cooperation with B Lymphocyte-Activating Factor

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