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      Role of the B7RP-1/ICOS Pathway in Renal Tubular Epithelial Antigen Presentation to CD4+ Th1 and Th2 Cells


      Cardiorenal Medicine

      S. Karger AG

      B7RP-1, Inducible costimulator, Tubular epithelial cells, Kidney, Th1, Th2

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          Background: IFN-γ-stimulated renal tubular epithelial cells (TECs) can present foreign protein antigen to T cells when stimulated with IFN-γ. TECs normally do not express B7, the ligand for the classical T-cell costimulatory molecule CD28, but express B7RP-1, the ligand of the inducible costimulator (ICOS). Methods: Flow cytometry was used to demonstrate expression of B7RP-1 on TECs, and expression of ICOS on A.E7 (Th1 clone) and D10.G4 (Th2 clone) cells. Using gene arrays, ELISA, and protein arrays, we examined the cytokine response of Th1 and Th2 subsets of CD4+ T cells in antigen presentation by IFN-γ-stimulated murine primary TECs. Results: In the presence of a specific foreign protein antigen, MHC-II-positive TECs induced clustering and a marked production of IFN-γ (A.E7) or IL-4 (D10.G4) by T cells. Blockade of the B7RP-1/ICOS pathway with specific monoclonal antibodies (mAbs) lead to a further increase in IFN-γ production by A.E7 cells, and a further increase in IL-4 production by D10.G4 cells as detected by gene array and ELISA. Protein arrays demonstrated an increase in Th2 cytokine levels upon blockade of the B7RP-1/ICOS pathway. Conclusions: These data show that the B7RP-1/ICOS interaction inhibits Th1 and Th2 T-cell responses in the setting of foreign antigen presentation by renal TECs. This inhibitory pathway may therefore serve as a negative feedback mechanism to inhibit immune-mediated tubulointerstitial renal disease.

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          Most cited references 5

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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 costimulatory molecule ICOS plays an important role in the immunopathogenesis of EAE.

            The inducible costimulatory molecule (ICOS) is expressed on activated T cells and participates in a variety of important immunoregulatory functions. After the induction of experimental allergic encephalomyelitis in SJL mice with proteolipid protein (PLP), brain ICOS mRNA and protein were up-regulated on infiltrating CD3+ T cells before disease onset. ICOS blockade during the efferent immune response (9-20 days after immunization) abrogated disease, but blockade during antigen priming (1-10 days after immunization) exacerbated disease. Upon culture with PLP and compared with immunized controls, splenocytes produced either decreased interferon-gamma (IFN-gamma, in efferent blockade) or excessive IFN-gamma (in priming blockade). PLP-specific immunoglobulin G1 was decreased in animals treated with anti-ICOS during antigen priming, but not in other groups.
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              Interferon γ Signaling Alters the Function of T Helper Type 1 Cells

              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.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                September 2004
                17 November 2004
                : 98
                : 1
                : e31-e38
                Division of Nephrology, Kantonsspital, St. Gallen, Switzerland
                79930 Nephron Exp Nephrol 2004;98:e31–e38
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 5, References: 27, Pages: 1
                Self URI (application/pdf):
                Original Paper

                Cardiovascular Medicine, Nephrology

                Kidney, Tubular epithelial cells, Th2, B7RP-1, Inducible costimulator, Th1


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