Publications (6)26.75 Total impact
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Article: Manipulation of CD98 resolves type 1 diabetes in nonobese diabetic mice.
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ABSTRACT: The interplay of CD4(+) and CD8(+) T cells targeting autoantigens is responsible for the progression of a number of autoimmune diseases, including type 1 diabetes mellitus (T1D). Understanding the molecular mechanisms that regulate T cell activation is crucial for designing effective therapies for autoimmune diseases. We probed a panel of Abs with T cell-modulating activity and identified a mAb specific for the H chain of CD98 (CD98hc) that was able to suppress T cell proliferation. The anti-CD98hc mAb also inhibited Ag-specific proliferation and the acquisition of effector function by CD4(+) and CD8(+) T cells in vitro and in vivo. Injection of the anti-CD98hc mAb completely prevented the onset of cyclophosphamide-induced diabetes in NOD mice. Treatment of diabetic NOD mice with anti-CD98hc reversed the diabetic state to normal levels, coincident with decreased proliferation of CD4(+) T cells. Furthermore, treatment of diabetic NOD mice with CD98hc small interfering RNA resolved T1D. These data indicate that strategies targeting CD98hc might have clinical application for treating T1D and other T cell-mediated autoimmune diseases.The Journal of Immunology 03/2012; 188(5):2227-34. · 5.79 Impact Factor -
Article: Notch2 regulates the development of marginal zone B cells through Fos.
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ABSTRACT: B cells are classified into several subsets depending on their functions, marker expression pattern and localization. Marginal zone B (MZB) cells are a distinct lineage from follicular B cells, and regulate host defenses against blood-borne pathogens. Notch2/RBP-J signaling regulates the development of MZB cells by interacting with delta-like 1 ligand, although the target genes for Notch2 signaling remain unclear. We identified Fos as an upregulated gene in LPS-stimulated B cells that received Notch2 signaling. Fos is expressed in CD21(high)CD23(low) MZB cells at a higher level compared to CD21(Int)CD23(high) follicular B cells. Deleting the Notch2 gene in CD19(+) B cells decreased Fos expression in B cells. Overexpression of Fos in Notch2-deficient B cells or bone marrow cells partially restored MZB development. Fos promoter activity was upregulated by Notch2 signaling, indicating that Notch2 directly controls Fos transcription associated with MZB development. These data identify Fos as one of the target genes for Notch2 signaling that is crucial for MZB development.Biochemical and Biophysical Research Communications 02/2012; 418(4):701-7. · 2.48 Impact Factor -
Article: Notch signaling regulates the development of a novel type of Thy1‐expressing dendritic cell in the thymus
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ABSTRACT: Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) required for T-cell activation and are classified into several subtypes by phenotypic and functional characteristics. However, it remains unclear if distinct transcription factors control the development of each DC subpopulation. In this report, we demonstrate that Notch signaling controls the development of a novel DC subtype that expresses Thy1 (Thy1+DCs). Overstimulation of bone marrow cells with the Notch ligand Delta-like 1 promoted the development of Thy1+DCs. Thy1+DCs are characterized as CD11c+MHC class II+NK1.1−B220−CD8α+, and are present in the thymus but not in the spleen and lymph nodes. Thymic Thy1+DCs are able to capture exogenous proteins and delete CD4+CD8+ T cells. Transplantation experiments demonstrated that CD44+CD25− and CD44+CD25+ thymocytes can differentiate into Thy1+DCs. Recombination signal binding protein for immunoglobulin kappa J region (RBP-J) deficiency in lineage-negative bone marrow cells, but not CD11c+ cells, disrupted Thy1+DC development in the thymus. Our data indicate that Notch signaling controls the development of a novel type of Thy1-expressing DC in the thymus that possibly controls negative selection, and indicates that there may be highly regulated, differential transcriptional control of DC development. Furthermore, our findings suggest that Notch signaling regulates T-cell development not only by intrinsically inducing T-cell lineage-specific gene programs, but also by regulating negative selection through Thy1+DCs.European Journal of Immunology 04/2011; 41(5):1309 - 1320. · 5.10 Impact Factor -
Article: Notch signaling regulates the development of a novel type of Thy1-expressing dendritic cell in the thymus.
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ABSTRACT: Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) required for T-cell activation and are classified into several subtypes by phenotypic and functional characteristics. However, it remains unclear if distinct transcription factors control the development of each DC subpopulation. In this report, we demonstrate that Notch signaling controls the development of a novel DC subtype that expresses Thy1 (Thy1(+) DCs). Overstimulation of bone marrow cells with the Notch ligand Delta-like 1 promoted the development of Thy1(+) DCs. Thy1(+) DCs are characterized as CD11c(+) MHC class II(+) NK1.1(-) B220(-) CD8α(+) , and are present in the thymus but not in the spleen and lymph nodes. Thymic Thy1(+) DCs are able to capture exogenous proteins and delete CD4(+) CD8(+) T cells. Transplantation experiments demonstrated that CD44(+) CD25(-) and CD44(+) CD25(+) thymocytes can differentiate into Thy1(+) DCs. Recombination signal binding protein for immunoglobulin kappa J region (RBP-J) deficiency in lineage-negative bone marrow cells, but not CD11c(+) cells, disrupted Thy1(+) DC development in the thymus. Our data indicate that Notch signaling controls the development of a novel type of Thy1-expressing DC in the thymus that possibly controls negative selection, and indicates that there may be highly regulated, differential transcriptional control of DC development. Furthermore, our findings suggest that Notch signaling regulates T-cell development not only by intrinsically inducing T-cell lineage-specific gene programs, but also by regulating negative selection through Thy1(+) DCs.European Journal of Immunology 02/2011; 41(5):1309-20. · 5.10 Impact Factor -
Article: Notch2 signaling is required for potent antitumor immunity in vivo.
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ABSTRACT: CD8(+) T cells play a central role in cancer immunosurveillance, and the efficient induction of CTLs against tumor Ags is required for successful immunotherapy for cancer patients. Notch signaling directly regulates the transcription of effector molecules in CTLs. However, it remains unclear whether Notch signaling in CD8(+) T cells is required for antitumor CTL responses and whether modulation of Notch signaling can augment antitumor CTL responses. In this study, we demonstrate that signaling by Notch2 but not Notch1 in CD8(+) T cells is required for antitumor CTL responses. Notch2(flox/flox) mice crossed with E8I-cre transgenic (N2F/F-E8I) mice, in which the Notch2 gene is absent only in CD8(+) T cells, die earlier than control mice after inoculation with OVA-expressing EG7 thymoma cells. In contrast, Notch1(flox/flox) mice crossed with E8I-cre transgenic mice inoculated with EG7 cells die comparable to control mice, indicating that Notch2 is crucial for exerting antitumor CTL responses. Injection of anti-Notch2 agonistic Ab or delta-like 1-overexpressing dendritic cells augmented the antitumor response in C57BL/6 mice inoculated with EG7 cells. These findings indicate that Notch2 signaling in CD8(+) T cells is required for generating potent antitumor CTLs, thus providing a crucial target for augmenting tumor immune responses.The Journal of Immunology 03/2010; 184(9):4673-8. · 5.79 Impact Factor -
Article: Protein-tyrosine phosphatase-kappa regulates CD4+ T cell development through ERK1/2-mediated signaling.
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ABSTRACT: T cells express diverse antigen-specific receptors and are required for eradicating pathogens and transformed cells. T cells expressing CD4 acquire helper effector functions and those expressing CD8 exert cytotoxic activity after antigen recognition. The protein-tyrosine phosphatase, receptor type kappa (PTPRKappa) is mutated in LEC rats, resulting in impaired CD4(+) T cell development in the thymus. However, the molecular mechanism of PTPRK controlling CD4(+) T cell development remains unclear. We demonstrate herein that inhibition of PTPRK by transducing a dominant negative form of the intracellular domain of PTPRK (PTPRK-ICD-DN) in bone marrow-derived stem cells suppresses the development of CD4(+) T cells. The inhibition of PTPRK by PTPRK-ICD-DN or short-hairpin RNA for PTPRK attenuates ERK1/2 phosphorylation in T cells after PMA and ionomycin stimulation. Total thymocytes from LEC rats also showed weaker phosphorylation of ERK1/2 after PMA and ionomycin stimulation than control thymocytes. Furthermore, inhibition of PTPRK by PTPRK-ICD-DN suppressed MEK1/2 and c-Raf phosphorylation, which is required for ERK1/2 phosphorylation. These data indicate that PPTRK positively regulates ERK1/2 phosphorylation, which impacts CD4(+) T cell development.Biochemical and Biophysical Research Communications 10/2009; 390(3):489-93. · 2.48 Impact Factor
