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ABSTRACT: Recurrent group A Streptococcus (GAS) tonsillitis and associated autoimmune diseases indicate that the immune response to this organism can be ineffective and pathological. TGF-beta1 is recognized as an essential signal for generation of regulatory T cells (Tregs) and T helper (Th) 17 cells. Here, the impact of TGF-beta1 induction on the T-cell response in mouse nasal-associated lymphoid tissue (NALT) following intranasal (i.n.) infections is investigated. ELISA and TGF-beta1-luciferase reporter assays indicated that persistent infection of mouse NALT with GAS sets the stage for TGF-beta1 and IL-6 production, signals required for promotion of a Th17 immune response. As predicted, IL-17, the Th17 signature cytokine, was induced in a TGF-beta1 signaling-dependent manner in single-cell suspensions of both human tonsils and NALT. Intracellular cytokine staining and flow cytometry demonstrated that CD4(+) IL-17(+) T cells are the dominant T cells induced in NALT by i.n. infections. Moreover, naive mice acquired the potential to clear GAS by adoptive transfer of CD4(+) T cells from immunized IL-17A(+)/(+) mice but not cells from IL-17A(-)/(-) mice. These experiments link specific induction of TGF-beta1 by a bacterial infection to an in vivo Th17 immune response and show that this cellular response is sufficient for protection against GAS. The association of a Th17 response with GAS infection reveals a potential mechanism for destructive autoimmune responses in humans.
Proceedings of the National Academy of Sciences 03/2010; 107(13):5937-42. · 9.68 Impact Factor
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ABSTRACT: Although regulatory CD4+CD25+ forkhead box p3+ (Foxp3+) T cells (Tregs) are generally thought to arise in the thymus as a separate lineage of CD4 T cells, they can also be induced de novo in the periphery. Peripheral development of Tregs from naïve T cells is favored by low-intensity activation and absence of inflammation. We show here that absence of CD28 costimulation results in a modest decrease in activation of naïve, antigen-specific CD4 T cells under noninflammatory conditions and benefits their initial Foxp3 induction. However, expression of Foxp3 following T cell activation without CD28 costimulation remains sensitive to the antigen dose. Furthermore, basal CD28 costimulation is critical for survival of the induced Foxp3+ CD4 T cells, and their accumulation is abrogated in the absence of CD28. In contrast, pharmacologic blockade of mammalian target of rapamycin enhances lasting induction of Tregs, irrespective of the initial antigen dose used to activate the antigen-specific T cells. This finding may have important practical, clinical implication in development of tolerance protocols.
Journal of Leukocyte Biology 06/2008; 83(5):1230-9. · 4.99 Impact Factor
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Xin Huang,
Hongfeng Guo, Johnthomas Kang,
Suet Choi,
Tom C Zhou,
Syam Tammana,
Christopher J Lees,
Zhong-Ze Li,
Michael Milone,
Bruce L Levine,
Jakub Tolar,
Carl H June,
R Scott McIvor,
John E Wagner,
Bruce R Blazar,
Xianzheng Zhou
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ABSTRACT: We have reported earlier that the non-viral Sleeping Beauty (SB) transposon system can mediate genomic integration and long-term reporter gene expression in human primary peripheral blood (PB) T cells. In order to test whether this system can be used for genetically modifying both PB T cells and umbilical cord blood (UCB) T cells as graft-versus-leukemia effector cells, an SB transposon was constructed to coexpress a single-chain chimeric antigen receptor (CAR) for human CD19 and CD20. PB and UCB were nucleofected with the transposon and a transposase plasmid, activated and then expanded in culture using anti-CD3/CD28 beads. Stable dual-gene expression was confirmed in both T-cell types, permitting enrichment by positive selection with Rituxan. The engineered CD4(+) T cells and CD8(+) T cells both exhibited specific cytotoxicity against CD19(+) leukemia and lymphoma cell lines, as well as against CD19 transfectants, and produced high-levels of antigen-dependent Th1 (but not Th2) cytokines. The in vivo adoptive transfer of genetically engineered T cells significantly reduced tumor growth and prolonged the survival of the animal. Taken together, these data indicate that T cells from PB and UCB can be stably modified using a non-viral DNA transfer system, and that such modified T cells may be useful in the treatment of refractory leukemia and lymphoma.
Molecular Therapy 04/2008; 16(3):580-9. · 6.87 Impact Factor
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ABSTRACT: There has been an alarming increase in the population diagnosed with diabetes worldwide. Although there is an ongoing debate as to the role of liver in the pathogenesis of diabetes, reduction of hepatic glucose production has been targeted as a strategy for diabetes treatment. Indeed, reduction of hepatic glucose production can be achieved through modulation of both hepatic and extra-hepatic targets. This review describes the role of the liver in the control of glucose homeostasis. Gluconeogenesis and glycogenolysis are pathways for glucose production, whereas glycolysis and glycogenesis are pathways for glucose utilization/storage. At the biochemical and molecular level, the metabolic and regulatory enzymes integrate hormonal and nutritional signals and regulate glucose flux in the liver. Modulating either activities of or gene expression of these metabolic enzymes can control hepatic glucose production. Dysfunction of one or several enzyme(s) due to insulin deficiency or resistance results in increases in fluxes of glycogenolysis and gluconeogenesis and/or decreases in fluxes of glycolysis and glycogenesis, which thereby lead to glucose generation exceeding glucose consumption/disposal, as well as dysregulation of lipid metabolism. Activation of enzymes that promote glucose utilization/storage and/or inhibition of enzymes that reduce glucose generation achieve reduction of hepatic glucose production, and hence lower levels of plasma glucose in diabetes. This is also beneficial for the correction of dyslipidemia. Therefore, many enzymes are viable therapeutic targets for diabetes.
Current Drug Targets - Immune Endocrine & Metabolic Disorders 04/2005; 5(1):51-9.
