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      Interferon γ Signaling Alters the Function of T Helper Type 1 Cells

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          Abstract

          One mechanism regulating the ability of different subsets of T helper (Th) cells to respond to cytokines is the differential expression of cytokine receptors. For example, Th2 cells express both chains of the interferon γ receptor (IFN-γR), whereas Th1 cells do not express the second chain of the IFN-γR (IFN-γR2) and are therefore unresponsive to IFN-γ. To determine whether the regulation of IFN-γR2 expression, and therefore IFN-γ responsiveness, is important for the differentiation of naive CD4 + T cells into Th1 cells or for Th1 effector function, we generated mice in which transgenic (TG) expression of IFN-γR2 is controlled by the CD2 promoter and enhancer. CD4 + T cells from IFN-γR2 TG mice exhibit impaired Th1 polarization potential in vitro. TG mice also display several defects in Th1-dependent immunity in vivo, including attenuated delayed-type hypersensitivity responses and decreased antigen-specific IFN-γ production. In addition, TG mice mount impaired Th1 responses against Leishmania major, as manifested by increased parasitemia and more severe lesions than their wild-type littermates. Together, these data suggest that the sustained expression of IFN-γR2 inhibits Th1 differentiation and function. Therefore, the acquisition of an IFN-γ–unresponsive phenotype in Th1 cells plays a crucial role in the development and function of these cells.

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          Most cited references 36

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          Determination of lymphocyte division by flow cytometry.

          Techniques currently available for determining cell division are able to show one or, at best, a limited number of cell divisions. Other methods exist which can quantify overall division, but tell nothing about the division history of individual cells. Here we present a new technique in which an intracellular fluorescent label is divided equally between daughter cells upon cell division. The technique is applicable to in vitro cell division, as well as in vivo division of adoptively transferred cells, and can resolve multiple successive generations using flow cytometry. The label is fluorescein derived, allowing monoclonal antibodies conjugated to phycoerythrin or other compatible fluorochromes to be used to immunophenotype the dividing cells.
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            Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches.

            T helper lymphocytes can be divided into two distinct subsets of effector cells based on their functional capabilities and the profile of cytokines they produce. The Th1 subset of CD4+ T cells secretes cytokines usually associated with inflammation, such as IFN-gamma and TNF and induces cell-mediated immune responses. The Th2 subset produces cytokines such as IL-4 and IL-5 that help B cells to proliferate and differentiate and is associated with humoral-type immune responses. The selective differentiation of either subset is established during priming and can be significantly influenced by a variety of factors. One of these factors, the cytokine environment, has been put forward as the major variable influencing Th development and is already well reviewed by others. Instead, in the current review, we focus on some of the alternative approaches for skewing Th1/Th2 responses. Specifically, we discuss the effects on Th priming of (a) using altered peptide ligands as antigens, (b) varying the dose of antigen, and (c) altering costimulatory signals. The potential importance of each of these variables to influence immune responses to pathogens in vivo is discussed throughout.
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              The regulation of immunity to Leishmania major.

              Experimental infection with the intracellular protozoan Leishmania major constitutes a particularly versatile model for assessing the role of CD4+ subset development in the host response to infectious disease. The association of Th1 development with control of infection, and of Th2 cell development with progressive disease, has been well established. The capacity to manipulate the outcome, using distinct immunologic interventions, in both genetically resistant and susceptible mice has identified key effector cytokines that must be present during the time of initial priming of T cells in order to affect the CD4 switch phenotype. Roles for interferon-gamma (IFN-gamma), interleukin 12 (IL-12), and IL-4 in Th1 and Th2 maturation have been demonstrated, although additional undefined signals are required. Study of the genetically susceptible BALB/c mouse has shown failure to downmodulate IL-4 production in response to infection, a response that is critically associated with the failure to develop appropriate Th1 responses. Use of the murine L. major model continues to elucidate new methods for vaccine development and suggests a promising system for identification of genes that determine susceptibility to infection.
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                Author and article information

                Contributors
                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                2 October 2000
                : 192
                : 7
                : 977-986
                Affiliations
                [a ]Integrated Program in Cell, Molecular and Biophysical Studies, the
                [b ]Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032
                [c ]Department of Microbiology, College of Physicians and Surgeons, Columbia University, New York, New York 10032
                [d ]Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032
                [e ]DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California 94304
                Article
                992191
                2193318
                11015439
                © 2000 The Rockefeller University Press
                Categories
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