The development of early and mature B cells is impaired in mice deficient for the Ets‐1 transcription factor

Eyquem, Stéphanie; Chemin, Karine; Fasseu, Magali; Chopin, Martine; Sigaux, François; Cumano, Ana; Borie, Raphaël

doi:10.1002/eji.200425352

Cited by 48 publications

(47 citation statements)

References 47 publications

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“…7A). This contrasts with the diminished survival reported for Ets1 knockout mice and complemented Rag2 Ϫ/Ϫ chimeras (12,40). These results suggest that dosage of Ets1 isoforms may be a critical modulator of apoptosis, as Ets1…”

Section: Discussioncontrasting

confidence: 64%

“…Surviving mice and chimeras derived from Ets1-targeted cells exhibit pan-lymphoid defects. These defects include reduced numbers of thymocytes, lymphoid cells in the spleen, and NK and NKT cells; loss of detectable NK and NKT cell activity; decreased proliferation and elevated apoptosis in mature T cells (4,6,40,58); increased differentiation of B cells to plasma cells with elevated serum immunoglobulin M; B-cell receptor signaling defects (12); abnormalities in T-cell receptor (TCR) ␤-selection in thymopoiesis; and an ineffective Th1 response (11,19). Complicating the assessment of Ets1 function is the fact that Ets1-null mice have been studied not only on a mixed genetic background (C57BL/6 ϫ 129Sv) predisposed to autoimmunity (53) but also with a line of Ets1-null mice that expresses a very low level of a neomorphic protein (ϳ1 to 5%) lacking the pointed domain of Ets1 (7,59).…”

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confidence: 99%

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Thymomegaly, Microsplenia, and Defective Homeostatic Proliferation of Peripheral Lymphocytes in p51-Ets1 Isoform-Specific Null Mice

Higuchi

Bartel

Masuya³

et al. 2007

Molecular and Cellular Biology

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Ets1 is a member of the Ets transcription factor family. Alternative splicing of exon VII results in two naturally occurring protein isoforms: full-length Ets1 (p51-Ets1) and Ets1⌬VII (p42-Ets1). These isoforms bear key distinctions regarding protein-protein interactions, DNA binding kinetics, and transcriptional target specificity. Disruption of both Ets1 isoforms in mice results in the loss of detectable NK and NKT cell activity and defects in B and T lymphocytes. We generated mice that express only the Ets1 ⌬VII isoform. Ets1⌬VII homozygous mice express no p51-Ets1 and elevated levels of the p42-Ets1 protein relative to the wild type and display increased perinatal lethality, thymomegaly, and peripheral lymphopenia. Proliferation was increased in both the thymus and the spleen, while apoptosis was decreased in the thymus and increased in the spleen of homozygotes. Significant elevations of CD8 ؉ and CD8 ؉ CD4 ؉ thymocytes were observed. Lymphoid cell (CD19 ؉ , CD4 ؉ , and CD8 ؉ ) reductions were predominantly responsible for diminished spleen cellularity, with fewer memory cells and a failure of homeostatic proliferation to maintain peripheral lymphocytes. Collectively, the Ets1⌬VII mutants demonstrate lymphocyte maturation defects associated with misregulation of p16 Ink4a , p27Kip1 , and CD44. Thus, a balance in the differential regulation of Ets1 isoforms represents a potential mechanism in the control of lymphoid maturation and homeostasis.

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Section: Discussioncontrasting

confidence: 64%

mentioning

confidence: 99%

Thymomegaly, Microsplenia, and Defective Homeostatic Proliferation of Peripheral Lymphocytes in p51-Ets1 Isoform-Specific Null Mice

Higuchi

Bartel

Masuya³

et al. 2007

Molecular and Cellular Biology

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“…More recently, Ets-1 has been shown to be important for optimal transition through early pre-TCR-dependent stages of thymocyte development and allelic exclusion at the TCR␤ locus (7). In the B cell compartment, Ets-1 deficiency results in impaired B cell development, an elevated frequency of IgM ϩ plasma cells in vivo and enhanced in vitro differentiation responses to CpG-containing oligonucleotide (a TLR9 ligand) (5,6,8,9). Ets-1-deficient mice produce both IgM and IgG autoantibodies leading to immune complex deposition in the kidney (5,8,9).…”

mentioning

confidence: 99%

“…In the B cell compartment, Ets-1 deficiency results in impaired B cell development, an elevated frequency of IgM ϩ plasma cells in vivo and enhanced in vitro differentiation responses to CpG-containing oligonucleotide (a TLR9 ligand) (5,6,8,9). Ets-1-deficient mice produce both IgM and IgG autoantibodies leading to immune complex deposition in the kidney (5,8,9). The numbers of splenic NK cells is also substantially reduced in Ets-1-deficient mice (10).…”

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confidence: 99%

Impaired Generation of CD8+ Thymocytes in Ets-1-Deficient Mice

Clements

John

Garrett‐Sinha

2006

The Journal of Immunology

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The Ets family of transcription factors function as key regulators of multiple aspects of immune cell development and function. To date, Ets-1 has been implicated in regulating early stages of thymic maturation and lymphocyte function and homeostasis. This report describes a novel role for Ets-1 in supporting later stages of thymic selection, in that positive selection of MHC class I-restricted CD4+CD8+ double-positive thymocytes is markedly inhibited in mice expressing a hypomorphic allele of Ets-1. This effect is thymocyte intrinsic, as Ets-1 mutant thymocytes fail to efficiently generate CD8+ single-positive thymocytes in mixed bone marrow chimeric backgrounds. Although peripheral CD8+ T cells are present in Ets-1 mutant mice, both CD4+ and CD8+ subsets contain an elevated proportion of cells with an effector memory (CD62L−CD44+) phenotype. In addition, while thymic expression of Thy1 is relatively normal, peripheral T cells isolated from Ets-1 mutant mice display a striking loss of Thy1 expression. These data identify Ets-1 as a key transcription factor regulating thymocyte positive selection and lineage commitment of MHC class I-restricted thymocytes.

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“…Instead, they had a novel B220 low , IgM + IgD -population, a 10-to 15-fold expansion of plasmacytes, increased expression of activation markers on follicular B cells, and a 10-fold increase in serum IgM levels [7][8][9]. B cell survival was normal in chimeric mice reconstituted with Ets1 -/-cells, although proliferative responses to anti-CD40 stimulation were halved [7].…”

Section: Cd8mentioning

confidence: 99%

Allelic Variation of Ets1 Does Not Contribute to NK and NKT Cell Deficiencies in Type 1 Diabetes Susceptible NOD Mice

Jordan

Poulton²,

Fletcher³

et al. 2009

Rev Diabet Stud

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■ AbstractThe NOD mouse strain is a well characterized model of type 1 diabetes that shares several of the characteristics of Ets1-deficient targeted mutant mice, viz: defects in TCR allelic exclusion, susceptibility to a lupus like disease characterized by IgM and IgG autoantibodies and immune complexmediated glomerulonephritis, and deficiencies of NK and NKT cells. Here, we sought evidence for allelic variation of Ets1 in mice contributing to the NK and NKT cell phenotypes of the NOD strain. ETS1 expression in NK and NKT cells was reduced in NOD mice, compared to C57BL/6 mice. Although NKT cells numbers were significantly correlated with ETS1 expression in both strains, NKT cell numbers were not linked to the Ets1 gene in a first backcross from NOD to C57BL/6 mice. These results indicate that allelic variation of Ets1 did not contribute to variation in NKT cell numbers in these mice. It remains possible that a third factor not linked to the Ets1 locus controls both ETS1 expression and subsequently NK and NKT cell phenotypes.

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The development of early and mature B cells is impaired in mice deficient for the Ets‐1 transcription factor

Abstract: The Ets-1 transcription factor is essential for normal development of the natural killer and T cell lineages; however, its role in B cell development remains poorly understood.

Cited by 48 publications

References 47 publications

Thymomegaly, Microsplenia, and Defective Homeostatic Proliferation of Peripheral Lymphocytes in p51-Ets1 Isoform-Specific Null Mice

Thymomegaly, Microsplenia, and Defective Homeostatic Proliferation of Peripheral Lymphocytes in p51-Ets1 Isoform-Specific Null Mice

Impaired Generation of CD8+ Thymocytes in Ets-1-Deficient Mice

Allelic Variation of Ets1 Does Not Contribute to NK and NKT Cell Deficiencies in Type 1 Diabetes Susceptible NOD Mice

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