The follicular versus marginal zone B lymphocyte cell fate decision

Pillai, Shiv; Cariappa, Annaiah

doi:10.1038/nri2656

Cited by 451 publications

(540 citation statements)

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“…Innate B cells, including marginal zone B (MZB) cells, which are initially committed by a weak BCR signal, activate NF-κB in response to stromal factors such as BAFF and Notch to provide signals for cell-fate decisions ( 33 ) and Ig switching ( 27 ). The similarities between MZB cells and CD5 + B cells suggest a common requirement for stroma-dependent NF-κB activation ( 34 ).…”

Section: Nets Stimulate Cd5 + B-cell Proliferation Via Nf-kbmentioning

confidence: 99%

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

et al. 2014

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Altered expression of matricellular proteins can become pathogenic in the presence of persistent perturbations in tissue homeostasis. Here, we show that autoimmunity associated with Fas mutation was exacerbated and transitioned to lymphomagenesis in the absence of SPARC (secreted protein acidic rich in cysteine). The absence of SPARC resulted in defective collagen assembly, with uneven compartmentalization of lymphoid and myeloid populations within secondary lymphoid organs (SLO), and faulty delivery of inhibitory signals from the extracellular matrix. These conditions promoted aberrant interactions between neutrophil extracellular traps and CD5 + B cells, which underwent malignant transformation due to defective apoptosis under the pressure of neutrophil-derived trophic factors and NF-κB activation. Furthermore, this model of defective stromal remodeling during lymphomagenesis correlates with human lymphomas arising in a SPARC-defective environment, which is prototypical of CD5 + B-cell chronic lymphocytic leukemia (CLL). SIGNIFICANCE:These results reveal the importance of stromal remodeling in SLO to accommodate autoimmune lymphoproliferation while preventing lymphomagenesis. Our fi ndings reveal a link between SPARC, collagen deposition, and the engagement of the immune-inhibitory receptor LAIR-1 on neutrophils, neutrophil cell death via NETosis, and the stimulation of CD5 + B-cell proliferation. Moreover, we show that SPARC defi ciency promotes CD5 + B-cell lymphomagenesis and is correlated with CLL in humans. Cancer Discov; 4(1);

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Section: Nets Stimulate Cd5 + B-cell Proliferation Via Nf-kbmentioning

confidence: 99%

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

et al. 2014

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“…Thirdly, the quality and the strength of the BCR repertoire determine whether positive selection of immature B cells by self ligands or microbiome derived ligands leads to deletion, FoB cell or MZB development [14][15][16]35 . It has been unclear how these three pathways are related.Pillai et al proposed that strong BCR signals favour FoB, whereas weak BCR signals promote MZB cell development 17,18,36,37 , although other investigators refuted this idea 11,15 . It was proposed that strong BCR signals render transitional cells in the follicle impervious to the presence of Dll1 mediated triggering of Notch2, whereas weak BCR signaling may enhance the expression of one or more components of the Notch2 signaling Although it is likely therefore that lack of MAPK mediated ADAM10 surface expression is the explanation for the MZB phenotype of Taok3-deficient mice, we also need to consider additional effects of Taok3 on MAPK-driven activation of NF-B, as canonical NF-B1 collaborates with Notch 2 in driving MZB fate determination 8 .…”

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confidence: 98%

“…We generated Taok3 equally important in B cell fate decisions [14][15][16] , and it was proposed that weak or strong BCR signals might render cells receptive or resistant to Notch instruction 17,18 . Yet how BCR repertoire or signaling controls Notch responsiveness is currently poorly understood.…”

Section: Notch2 and B Cell Antigen Receptor (Bcr) Signaling Determinementioning

confidence: 99%

Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10

et al. 2017

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2 Notch2 and B cell antigen receptor (BCR) signaling determine if transitional B cells become marginal zone B (MZB) or follicular B (FoB) cells in the spleen, but it isunknown how these pathways are related. We generated Taok3 equally important in B cell fate decisions [14][15][16] , and it was proposed that weak or strong BCR signals might render cells receptive or resistant to Notch instruction 17,18 . Yet how BCR repertoire or signaling controls Notch responsiveness is currently poorly understood.The Ste20 family kinases are serine-threonine kinases that participate in a variety of signaling pathways triggered by cellular stress 19,20 . The Tao kinase subfamily has three members in mammals (TAOK1, also known as proteins MAP3K16, PSK2 or MARKK; TAOK2 (MAP3K17, PSK1) and TAOK3 (MAP3K18, JIK or DPK)), whose function is largely unknown. Here, we generated Taok3 -/-mice and found that these mice lacked MZB cells, whereas FoB cells were intact. By carefully unraveling the molecular mechanism of this deficiency we have discovered how BCR signaling intersects with Notch signaling in immature transitional B cells undergoing positive selection. RESULTS 4 Taok3 -/-mice lack MZB cellsIn wild-type mice, the expression of mRNA for Taok3 was predominantly found in bone marrow and immune tissues like spleen, thymus and lymph nodes, but also in lung and gut (Fig. 1a). To gain insight into the biology of Taok3, we generated Taok3 -/-mice ( Supplementary Fig. 1a-e). Overall there was no difference in the cellularity of the various lymphoid organs in 6-12 week old mice (Supplementary Fig. 1f). In the spleen, there were no gross differences in the percentage of eosinophils, monocytes, natural killer (NK) cells and NKT cells between Taok3 -/-and wild-type mice, yet there was a consistent reduction in the amount of CD11c + dendritic cells in Taok3 -/-mice (Fig. 1b).There was a small yet consistent increase in the percentage of Ly6G + granulocytes in the spleen of Taok3 -/-mice. The distribution of CD3 + T cells and CD19 + B cells was comparable, yet there was a 25-30% reduction in the amount of CD8 + T cells (Fig. 1c). (Fig. 1d-f).Histological examination of the spleen revealed that the characteristic rim of IgM + CD1d + MZB cells separated from the IgM lo B cell follicles by the marginal sinus was absent in Taok3 -/-mice (Fig. 1g). Resident marginal zone metallophillic macrophages (MMM, expressing CD169) that line the marginal sinus were present and correctly localized in Taok3 -/-mice (Fig. 1h) (Fig. 1h). Collectively, Taok3 -/-mice lack MZB cells without compensatory alterations in other B cell subsets. Humoral immune response of Taok3 -/-miceThe baseline serum concentration of immunoglobulins (Ig) was comparable to wild-type, with a tendency for increased IgG3 in Taok3 -/-mice (Supplementary Fig 2) Fig. 1i and Supplementary Fig 2 ). The intact TNPspecific Ig response as not due to compensatory increase in recirculating MZB cells outside the spleen (data not shown). B1 B cells can also respond to TNP-Ficoll antigen, in the com...

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“…So far Bcl-3 has also been implicated in various gene regulatory networks and biological processes [6,7] but its physiological mechanisms of action and in vivo targets remain largely unknown. from the bone marrow into the spleen develop through distinct transitional B-cell stages, termed as T1, T2, and T3 [11]. The T2 transitional B cell is thought to be the common precursor for both MZ and FO B cells [12].…”

Section: Introductionmentioning

confidence: 99%

“…Immature B cells that emigrate * These authors contributed equally to this work. from the bone marrow into the spleen develop through distinct transitional B-cell stages, termed as T1, T2, and T3 [11]. The T2 transitional B cell is thought to be the common precursor for both MZ and FO B cells [12].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Bcl‐3 inhibits the development of marginal zone B cells

et al. 2013

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The transcription factor Bcl-3 functions as a proto-oncogene via regulation of cell proliferation and apoptosis. Bcl-3 is an atypical member of the IκB family and plays a central role in the immune response through interactions with the NF-κB subunits p50 and p52. To investigate the impact of Bcl-3 on B-cell maturation and regulation, we generated mice that overexpress Bcl-3 specifically in B cells. Interestingly, these mice lack marginal zone B cells and exhibit a significant reduction in the number of B-1 B cells. Further, B cells from these mice are impaired in their proliferative capacity. Our data demonstrate that the overexpression of the transcription factor Bcl-3 inhibits germinal center formation, marginal zone B-cell development, and affects the B-1 B-cell compartment.Keywords: B-1 B cells r Bcl-3 r Marginal zone B cell r NF-κB Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe Bcl-3 gene was first identified in a translocation into the Ig alpha locus in various cases of B-cell chronic lymphocytic leukemia [1,2]. The oncogene Bcl-3 encodes for an atypical member of the inhibitor of kappa B (IκB) family of proteins. Although Bcl-3 has high structural homology to the other IκB family members, Bcl-3 fails to inhibit NF-κB molecules in the cytoplasm but instead is a nuclear protein with both activating and repressing functions [3,4]. Specific domains within Bcl-3 can stimulate transcription through interaction with p50 and p52 homodimers [3,5]. So far Bcl-3 has also been implicated in various gene regulatory networks and biological processes [6,7] but its physiological mechanisms of action and in vivo targets remain largely unknown.Correspondence: Dr. Nadine Hövelmeyer e-mail: hoevelme@uni-mainz. de In order to study the role of Bcl-3 in lymphoid malignancies, Tg animals were generated overexpressing Bcl-3 in B and T cells. These mice exhibit splenomegaly and an accumulation of mature B cells in secondary lymphoid organs, but fail to develop lymphoid neoplasms. These mice show an increased response to crosslinking of surface IgM [8]. On the other hand, Bcl-3-deficient mice demonstrate the requirement for Bcl-3 in germinal center (GC) formation and in the production of Ag-specific antibodies [9,10]. Naïve B cells are generally divided into three subsets, B-1 B cells, follicular (FO), and marginal zone (MZ) B cells, whereas MZ B cells play a central role in eliciting Ab response against bloodborn pathogens. These B cells reside within the MZ located outside the marginal sinus and are the juncture of white and red pulp in the spleen. The factors that regulate the homeostasis of MZ B cells are not completely understood. Immature B cells that emigrate * These authors contributed equally to this work. from the bone marrow into the spleen develop through distinct transitional B-cell stages, termed as T1, T2, and T3 [11]. The T2 transitional B cell is thought to be the common precursor for both MZ and FO B cells [12]. FO B cells can b...

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The follicular versus marginal zone B lymphocyte cell fate decision

Cited by 451 publications

References 105 publications

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10

Overexpression of Bcl‐3 inhibits the development of marginal zone B cells

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