ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo

Gibb, David R.; Shikh, Mohey Eldin El; Kang, Dae Joong; Rowe, Warren; Sayed, Rania; Cichy, Joanna; Yagita, Hideo; Tew, John G.; Dempsey, Peter J.; Crawford, Howard C.; Conrad, Daniel H.

doi:10.1084/jem.20091990

Cited by 137 publications

(163 citation statements)

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“…It was long held that MZB cells emanate from progenitors with a CD23 + T2B phenotype that express CD1d and CD21 6,10,17,41 . Others have also proposed that FoB cells can develop into MZB cells, particularly in immunodeficient and lymphopenic hosts, a process that might be driven by homeostatic proliferation 24,41,42 .…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…5). ADAM10 is known to cleave substrates when expressed on the cell surface, and we have reported that ADAM10 can be detected by flow cytometry on lymphocytes 10 . We found that 5-6% of CD93 + transitional B cells of the spleen of wild-type mice expressed ADAM10 on their cell surface, yet this expression was almost completely absent in Taok3 -/-mice 9 (Fig.…”

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confidence: 96%

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

et al. 2017

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“…Previous studies have shown that ADAM10 and ADAM28 may be essential for Notch2‐dependent MZ B‐cell development 26, 27, 28. qRT‐PCR analysis showed that Transitional B cells expressed the high level of ADAM10, whereas MZP B cells expressed the high level of ADAM28 (Fig.…”

Section: Resultsmentioning

confidence: 77%

“…ADAM10 has been shown to be essential for the development of MZ B cells 28. A recent study demonstrated that T1 B cells expressing surface ADAM10 were committed to becoming MZB cells in vivo , whereas T1 B cells lacking expression of ADAM10 were not 26.…”

Section: Discussionmentioning

confidence: 99%

CD19 regulates ADAM28‐mediated Notch2 cleavage to control the differentiation of marginal zone precursors to MZ B cells

Zhu

Xiao²,

Liu³

et al. 2017

J Cellular Molecular Medi

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As the first line of defence, marginal zone (MZ) B cells play principal roles in clearing blood‐borne pathogens during infection and are over‐primed in autoimmune diseases. However, the basic mechanisms underlying MZ B‐cell development are still unclear. We found here that CD19 deficiency blocked the differentiation of marginal zone precursors (MZP) to MZ B cells, whereas CD19 expression in CD19‐deficient MZP rescues MZ B‐cell generation. Furthermore, CD19 regulates Notch2 cleavage by up‐regulating ADAM28 expression in MZP. Finally, we found that CD19 suppressed Foxo1 expression to promote ADAM28 expression in MZP. These results suggest that CD19 controls the differentiation of MZP to MZ B cells by regulating ADAM28‐mediated Notch2 cleavage. Thus, we demonstrated the basic mechanisms underlying the differentiation of MZP to MZ B cells.

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“…FO B cells can be further subdivided into FOI and FOII B cells, where the latter represent long-lived recirculating B cells that were suggested to serve as a reservoir to replenish MZ B cells [13]. Tg animal models have identified several determinants important for MZ B-cell development and maintenance, including Notch [14,15], NF-κB [9,16], and BCR signaling [17,18]. In order to unravel the role of Bcl-3 in B cells, we generated mice that overexpress Bcl-3 specifically in B cells.…”

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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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ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo

Cited by 137 publications

References 56 publications

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

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

CD19 regulates ADAM28‐mediated Notch2 cleavage to control the differentiation of marginal zone precursors to MZ B cells

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

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