IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity

Simonetti, Giorgia; Carette, Amanda; Silva, Kathryn; Wang, Haowei; Silva, Nilushi S. De; Heise, Nicole; Siebel, Christian W.; Shlomchik, Mark J.; Klein, Ulf

doi:10.1084/jem.20131026

Cited by 62 publications

(81 citation statements)

References 62 publications

(101 reference statements)

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“…B1 cells derive from fetal progenitors and react to a restricted set of microbial ligands in a T cell-independent (TI) manner in serosal cavities and spleen 1 NF-B signaling emanating from the BAFF receptor [2][3][4][5][6][7][8][9][10][11][12][13] . The quality of B cell antigen receptor (BCR) signals during positive selection of B cell precursors in the spleen is 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 .…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…IRF4-deficiency caused upregulation of NOTCH2 and replacement of mature B cells from the follicle into the MZ. 33 Here, we isolated mRNA from Em-Tcl1 and Cxcr5 ¡/¡ Em-Tcl1 cells 3 d after transfer and found that NOTCH2 expression was higher in Cxcr5 ¡/¡ Em-Tcl1 cells, whereas IRF4 expression was reduced (Fig. 6B).…”

Section: Differential Surface Expression Of Adhesion Molecules Is Regmentioning

confidence: 79%

“…37 We additionally found enhanced expression of NOTCH2. Activation of the NOTCH2 pathway has been linked to B cell retention in the MZ 33 and constitutive expression of active NOTCH2 gives rise to increased numbers of MZ versus follicular B cells. 38 ALCAM, which is downregulated in MZ versus follicular B cells, 33,39 was also downregulated on Cxcr5 ¡/¡ Em-Tcl1 compared with follicular-located Em-Tcl1 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of the NOTCH2 pathway has been linked to B cell retention in the MZ 33 and constitutive expression of active NOTCH2 gives rise to increased numbers of MZ versus follicular B cells. 38 ALCAM, which is downregulated in MZ versus follicular B cells, 33,39 was also downregulated on Cxcr5 ¡/¡ Em-Tcl1 compared with follicular-located Em-Tcl1 cells. In support of the gene expression data, differences in surface expression levels between leukemic cells derived from Cxcr5 ¡/¡ Em-Tcl1 or Em-Tcl1 mice were confirmed for CD49d, ALCAM, and NOTCH2.…”

Section: Discussionmentioning

confidence: 99%

“…33 The authors concluded that IRF4 controls the positioning of B cells in SLOs by regulating NOTCH2 expression. However, a causal molecular link of how IRF4 regulates NOTCH2 expression was not provided.…”

Section: Discussionmentioning

confidence: 99%

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The splenic marginal zone shapes the phenotype of leukemia B cells and facilitates their niche-specific retention and survival

et al. 2017

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Microenvironmental regulation in lymphoid tissues is essential for the development of chronic lymphocytic leukemia. We identified cellular and molecular factors provided by the splenic marginal zone (MZ), which alter the migratory and adhesive behavior of leukemic cells. We used the Cxcr5 ¡/¡ Em-Tcl1 leukemia mouse model, in which tumor cells are excluded from B cell follicles and instead accumulate within the MZ. Genes involved in MZ B cell development and genes encoding for adhesion molecules were upregulated in MZ-localized Cxcr5 ¡/¡ Em-Tcl1 cells. Likewise, surface expression of the adhesion and homing molecules, CD49d/VLA-4 and CXCR7, and of NOTCH2 was increased. In vitro, exposing Em-Tcl1 cells or human CLL cells to niche-specific stimuli, like B cell receptor-or Toll-like receptor ligands, caused surface expression of these molecules characteristic for a follicular or MZ-like microenvironment, respectively. In vivo, inhibition of VLA-4-mediated adhesion and CXCL13-mediated follicular homing displaced leukemic cells not only from the follicle, but also from the MZ and reduced leukemia progression. We conclude that MZ-specific factors shape the phenotype of leukemic cells and facilitate their niche-specific retention. This strong microenvironmental influence gains pathogenic significance independent from tumor-specific genetic aberrations.

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Notch signaling at the crossroads of innate and adaptive immunity

Vanderbeck

Maillard

2020

Journal of Leukocyte Biology

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Notch signaling is an evolutionarily conserved cell-to-cell signaling pathway that regulates cellular differentiation and function across multiple tissue types and developmental stages. In this review, we discuss our current understanding of Notch signaling in mammalian innate and adaptive immunity. The importance of Notch signaling is pervasive throughout the immune system, as it elicits lineage and context-dependent effects in a wide repertoire of cells. Although regulation of binary cell fate decisions encompasses many of the functions first ascribed to Notch in the immune system, recent advances in the field have refined and expanded our view of the Notch pathway beyond this initial concept. From establishing T cell identity in the thymus to regulating mature T cell function in the periphery, the Notch pathway is an essential, recurring signal for the T cell lineage. Among B cells, Notch signaling is required for the development and maintenance of marginal zone B cells in the spleen. Emerging roles for Notch signaling in innate and innate-like lineages such as classical dendritic cells and innate lymphoid cells are likewise coming into view. Lastly, we speculate on the molecular underpinnings that shape the activity and versatility of the Notch pathway.

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IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity

Abstract: The transcription factor IRF4 limits the retention of B cells in the marginal zone by inhibiting NOTCH2 signaling.

Cited by 62 publications

References 62 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

The splenic marginal zone shapes the phenotype of leukemia B cells and facilitates their niche-specific retention and survival

Notch signaling at the crossroads of innate and adaptive immunity

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