Center for Cancer and Immunology Research

Washington, DC, United States

Center for Cancer and Immunology Research

Washington, DC, United States
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Thaxton J.E.,Medical University of South Carolina | Liu B.,Medical University of South Carolina | Zheng P.,Center for Cancer and Immunology Research | Liu Y.,Center for Cancer and Immunology Research | Li Z.,Medical University of South Carolina
Journal of Immunology | Year: 2014

CD24 binds to and suppresses inflammation triggered by danger-associated molecular patterns such as heat shock proteins (HSPs) and high-mobility group box 1. Paradoxically, CD24 has been shown to enhance autoimmune disease. In this study, we attempt to reconcile this paradox by deletion of CD24 (24KO) in a lupus-like disease model driven by forced expression of HSP gp96 at the cell surface (transgenic mice [tm]). As expected, tm24KO mice showed increased CD11c+ dendritic cell activation coupled to a significant increase in dendritic cell-specific IL-12 production compared with tm mice. However, tm24KO mice showed less CD4 T cell activation and peripheral inflammatory cytokine production in comparison with tm mice. We characterized an enhanced immune suppressive milieu in tm24KO mice distinguished by increased TGF-β and greater regulatory T cell-suppressive capacity. We found greater absolute numbers of myeloid-derived suppressor cells (MDSCs) in tm24KO mice and showed that the Ly6C+ MDSC subset had greater suppressive capacity from tm24KO mice. Deletion of CD24 in tm mice led to diminished lupus-like pathology as evidenced by anti-nuclear Ab deposition and glomerulonephritis. Finally, we show that expanded MDSC populations were mediated by increased free high-mobility group box 1 in tm24KO mice. Thus, the deletion of CD24 in an HSPdriven model of autoimmunity led to the unexpected development of regulatory T cell and MDSC populations that augmented immune tolerance. Further study of these populations as possible negative regulators of inflammation in the context of autoimmunity is warranted. Copyright © 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.

Chen G.-Y.,Center for Cancer and Immunology Research | Brown N.K.,Center for Cancer and Immunology Research | Wu W.,Center for Cancer and Immunology Research | Khedri Z.,University of California at Davis | And 7 more authors.
eLife | Year: 2014

Both pathogen- and tissue damage-associated molecular patterns induce inflammation through toll-like receptors (TLRs), while sialic acid-binding immunoglobulin superfamily lectin receptors (Siglecs) provide negative regulation. Here we report extensive and direct interactions between these pattern recognition receptors. The promiscuous TLR binders were human SIGLEC-5/9 and mouse Siglec-3/E/F. Mouse Siglec-G did not show appreciable binding to any TLRs tested. Correspondingly, Siglece deletion enhanced dendritic cell responses to all microbial TLR ligands tested, while Siglecg deletion did not affect the responses to these ligands. TLR4 activation triggers Neu1 translocation to cell surface to disrupt TLR4:Siglec-E interaction. Conversely, sialidase inhibitor Neu5Gc2en prevented TLR4 ligand-induced disruption of TLR4:Siglec E/F interactions. Absence of Neu1 in hematopoietic cells or systematic treatment with sialidase inhibitor Neu5Gc2en protected mice against endotoxemia. Our data raised an intriguing possibility of a broad repression of TLR function by Siglecs and a sialidase-mediated de-repression that allows positive feedback of TLR activation during infection. © 2014, Chen et al.

Ye P.,Center for Cancer and Immunology Research | Liu Y.,Sichuan University | Chen C.,Sichuan University | Tang F.,Center for Cancer and Immunology Research | And 7 more authors.
Molecular Cell | Year: 2015

mTOR senses nutrient and energy status to regulate cell survival and metabolism in response to environmental changes. Surprisingly, targeted mutation of Tsc1, a negative regulator of mTORC1, caused a broad reduction in miRNAs due to Drosha degradation. Conversely, targeted mutation of Raptor, an essential component of mTORC1, increased miRNA biogenesis. mTOR activation increased expression of Mdm2, which is hereby identified as the necessary and sufficient ubiquitin E3 ligase for Drosha. Drosha was induced by nutrient and energy deprivation and conferred resistance to glucose deprivation. Using a high-throughput screen of a miRNA library, we identified four miRNAs that were necessary and sufficient to protect cells against glucose-deprivation-induced apoptosis. These miRNA was regulated by glucose through the mTORC1-MDM2-DROSHA axis. Taken together, our data reveal an mTOR-Mdm2-Drosha pathway in mammalian cells that broadly regulates miRNA biogenesis as a response to alteration in cellular environment. © 2015 Elsevier Inc.

Ichiyama K.,Center for Cancer and Immunology Research | Chen T.,Sun Yat Sen University | Wang X.,Tsinghua University | Yan X.,Institute for Systems Biology | And 10 more authors.
Immunity | Year: 2015

Epigenetic regulation of lineage-specific genes is important for the differentiation and function of Tcells. Ten-eleven translocation (Tet) proteins catalyze 5-methylcytosine (5mC) conversion to 5-hydroxymethylcytosine (5hmC) to mediate DNA demethylation. However, the roles of Tet proteins in the immune response are unknown. Here, we characterized the genome-wide distribution of 5hmC in CD4+ Tcells and found that 5hmC marks putative regulatory elements in signature genes associated with effector cell differentiation. Moreover, Tet2 protein was recruited to 5hmC-containing regions, dependent on lineage-specific transcription factors. Deletion of Tet2 in Tcells decreased their cytokine expression, associated with reduced p300 recruitment. Invivo, Tet2 plays a critical role in the control of cytokine gene expression in autoimmune disease. Collectively, our findings suggest that Tet2 promotes DNA demethylation and activation of cytokine gene expression in Tcells. © 2015 Elsevier Inc.

Brown N.K.,University of Michigan | Brown N.K.,Center for Cancer and Immunology Research | Zhou Z.,University of Michigan | Zhang J.,University of Michigan | And 5 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2014

Perivascular adipose tissue (PVAT), long assumed to be nothing more than vessel-supporting connective tissue, is now understood to be an important, active component of the vasculature, with integral roles in vascular health and disease. PVAT is an adipose tissue with similarities to both brown and white adipose tissue, although recent evidence suggests that PVAT develops from its own precursors. Like other adipose tissue depots, PVAT secretes numerous biologically active substances that can act in both autocrine and paracrine fashion. PVAT has also proven to be involved in vascular inflammation. Although PVAT can support inflammation during atherosclerosis via macrophage accumulation, emerging evidence suggests that PVAT also has antiatherosclerotic properties related to its abilities to induce nonshivering thermogenesis and metabolize fatty acids. We here discuss the accumulated knowledge of PVAT biology and related research on models of hypertension and atherosclerosis. © 2014 American Heart Association, Inc.

Li W.,University of Michigan | Katoh H.,Hokkaido University | Wang L.,University of Alabama at Birmingham | Yu X.,University of Michigan | And 4 more authors.
Cancer Research | Year: 2013

FOXP3 is an X-linked tumor suppressor gene and a master regulator in T regulatory cell function. This gene has been found to be mutated frequently in breast and prostate cancers and to inhibit tumor cell growth, but its functional significance in DNA repair has not been studied. We found that FOXP3 silencing stimulates homologous recombination-mediated DNA repair and also repair of g-irradiation-induced DNA damage. Expression profiling and chromatin- immunoprecipitation analyses revealed that FOXP3 regulated the BRCA1-mediated DNA repair program. Among 48 FOXP3-regulated DNA repair genes, BRCA1 and 12 others were direct targets of FOXP3 transcriptional control. Site-specific interaction of FOXP3 with the BRCA1 promoter repressed its transcription. Somatic FOXP3 mutants identified in breast cancer samples had reduced BRCA1 repressor activity, whereas FOXP3 silencing and knock-in of a prostate cancer-derived somatic FOXP3 mutant increased the radioresistance of cancer cells. Together our findings provide a missing link between FOXP3 function and DNA repair programs. © 2012 American Association for Cancer Research.

Geng X.,University of Arkansas at Little Rock | Wu W.,University of Arkansas at Little Rock | Li N.,Center for Cancer and Immunology Research | Sun W.,University of Arkansas at Little Rock | And 5 more authors.
Advanced Functional Materials | Year: 2014

The hydrogen evolution reaction in an alkaline environment using a nonprecious catalyst with much greater efficiency represents a critical challenge in research. Here, a robust and highly active system for hydrogen evolution reaction in alkaline solution is reported by developing MoS2 nanosheet arrays vertically aligned on graphene-mediated 3D Ni networks. The catalytic activity of the 3D MoS2 nanostructures is found to increase by 2 orders of magnitude as compared to the Ni networks without MoS2. The MoS2 nanosheets vertically grow on the surface of graphene by employing tetrakis(diethylam inodithiocarbomato)molybdate(IV) as the molybdenum and sulfur source in a chemical vapor deposition process. The few-layer MoS2 nanosheets on 3D graphene/nickel structure can maximize the exposure of their edge sites at the atomic scale and present a superior catalysis activity for hydrogen production. In addition, the backbone structure facilitates as an excellent electrode for charge transport. This precious-metal-free and highly efficient active system enables prospective opportunities for using alkaline solution in industrial applications. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Liu Y.,Center for Cancer and Immunology Research | Liu Y.,George Washington University | Wondimu A.,Center for Cancer and Immunology Research | Yan S.,Center for Cancer and Immunology Research | And 3 more authors.
Angiogenesis | Year: 2014

Tumor cells shed gangliosides and populate their microenvironment with these biologically active membrane glycosphingolipids. In vitro, ganglioside enrichment amplifies receptor tyrosine kinase signaling and activation of vascular endothelial cells. However, a long-standing question is whether in the actual microenvironment of a neoplasm, in vivo, tumor cell ganglioside shedding stimulates angiogenesis. Here we tested the hypothesis that tumor gangliosides have a critical proangiogenic role in vivo using novel murine tumor cells, GM3synthase/GM2synthase double knockout (DKO) cells, genetically completely incapable of ganglioside synthesis and impaired in tumor growth versus wild-type (WT) ganglioside-rich cells. We studied angiogenesis during tumor formation by these ganglioside-depleted cells, quantifying vessel formation, angiogenic factor production/release, and consequences of reconstitution with purified WT gangliosides. DKO cells formed virtually avascular tumors, much smaller than ganglioside-rich WT tumors and displaying a striking paucity of blood vessels, despite levels of VEGF and other angiogenic factors that were similar to those of WT cells. Transient enrichment of the ganglioside milieu of the DKO cell inoculum by adding purified WT gangliosides partially restored angiogenesis and tumor growth. We conclude that tumor gangliosides trigger robust angiogenesis important for tumor growth. Our findings suggest strategies to eliminate their synthesis and shedding by tumor cells should be pursued. © 2013 Springer Science+Business Media Dordrecht.

Katoh H.,Hokkaido University | Zheng P.,University of Michigan | Liu Y.,Center for Cancer and Immunology Research
Journal of Autoimmunity | Year: 2013

FOXP3 plays an essential role in the maintenance of self-tolerance and, thus, in preventing autoimmune diseases. Inactivating mutations of FOXP3 cause immunodysregulation, polyendocrinopathy, and enteropathy, X-linked syndrome. FOXP3-expressing regulatory T cells attenuate autoimmunity as well as immunity against cancer and infection. More recent studies demonstrated that FOXP3 is an epithelial cell-intrinsic tumor suppressor for breast, prostate, ovary and other cancers. Corresponding to its broad function, FOXP3 regulates a broad spectrum of target genes. While it is now well established that FOXP3 binds to and regulates thousands of target genes in mouse and human genomes, the fundamental mechanisms of its broad impact on gene expression remain to be established. FOXP3 is known to both activate and repress target genes by epigenetically regulating histone modifications of target promoters. In this review, we first focus on germline mutations found in the FOXP3 gene among IPEX patients, then outline possible molecular mechanisms by which FOXP3 epigenetically regulates its targets. Finally, we discuss clinical implications of the function of FOXP3 as an epigenetic modifier. Accumulating results reveal an intriguing functional convergence between FOXP3 and inhibitors of histone deacetylases. The essential epigenetic function of FOXP3 provides a foundation for experimental therapies against autoimmune diseases. © 2013 Elsevier Ltd.

Zheng P.,University of Michigan | Chang X.,La Jolla Institute for Allergy and Immunology | Lu Q.,Central South University | Liu Y.,Center for Cancer and Immunology Research
Journal of Autoimmunity | Year: 2013

A long-standing but poorly understood defect in autoimmune diseases is dysfunction of the hematopoietic cells. Leukopenia is often associated with systemic lupus erythematous (SLE) and other autoimmune diseases. In addition, homeostatic proliferation of T cells, which is a host response to T-cell lymphopenia, has been implicated as potential cause of rheumatoid arthritis (RA) in human and experimental models of autoimmune diabetes in the NOD mice and the BB rats. Conversely, successful treatments of aplastic anemia by immune suppression suggest that the hematologic abnormality may have a root in autoimmune diseases. Traditionally, the link between autoimmune diseases and defects in hematopoietic cells has been viewed from the prism of antibody-mediated hemolytic cytopenia. While autoimmune destruction may well be part of pathogenesis of defects in hematopoietic system, it is worth considering the hypothesis that either leukopenia or pancytopenia may also result directly from defective hematopoietic stem cells (HSC). We have recently tested this hypothesis in the autoimmune Scurfy mice which has mutation Foxp3, the master regulator of regulatory T cells. Our data demonstrated that due to hyperactivation of mTOR, the HSC in the Scurfy mice are extremely poor in hematopoiesis. Moreover, rapamycin, an mTOR inhibitor rescued HSC defects and prolonged survival of the Scurfy mice. Our data raised the intriguing possibility that targeting mTOR dysregulation in the HSC may help to break the vicious cycle between cytopenia and autoimmune diseases. © 2013 Elsevier Ltd.

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