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      TGF-Beta Treatment Modulates PD-L1 and CD40 Expression in Proximal Renal Tubular Epithelial Cells and Enhances CD8 + Cytotoxic T-Cell Responses

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          Abstract

          Background/Aim: TGF-β expression is increased in immune-mediated and fibrotic renal diseases and modulates the tubulointerstitial T-cell response. We examined whether TGF-β changes the expression of PD-L1 and CD40 in the renal proximal tubular epithelial cell (TEC), and whether the activation of CD8<sup>+</sup> cytotoxic T cells (CTLs) is influenced by TGF-β treatment of TECs. Methods: Murine TECs were treated with TGF-β or IFN-γ. The expression of PD-L1 and CD40 was examined with RT-PCR and flow cytometry. To investigate if TGF-β treatment influenced the antigen presentation capacity of TECs, OT-1 CTLs were co-incubated with TGF-β-treated, OVA<sub>257–264</sub> peptide-pulsed congeneic TECs. The cytotoxicity of OT-1 CTLs was estimated by their capacity to produce IFN-γ and their cytolytic activity. Results: TGF-β treatment lead to a transition in morphology of renal TECs and downregulated the basal and the IFN-γ-stimulated PD-L1 expression in TECs. Interestingly, TGF-β treatment of TECs increased the constitutive and IFN-γ-induced CD40 expression. In contrast to IFN-γ which reduced the CTL activity, TGF-β treatment of TECs elevated the OVA-specific CTL response. Conclusion: Our data show that TGF-β changed the cellular phenotype and the expression of PD-L1 and CD40 on TECs and enhanced the activity of OVA peptide-specific CD8<sup>+</sup> T cells. TGF-β may thereby play an important role in the progression of renal tubulointerstitial damage in CD8<sup>+</sup> T-cell-mediated renal diseases.

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          Most cited references 24

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          T cell receptor antagonist peptides induce positive selection.

          We have used organ culture of fetal thymic lobes from T cell receptor (TCR) transgenic beta 2M(-/-) mice to study the role of peptides in positive selection. The TCR used was from a CD8+ T cell specific for ovalbumin 257-264 in the context of Kb. Several peptides with the ability to induce positive selection were identified. These peptide-selected thymocytes have the same phenotype as mature CD8+ T cells and can respond to antigen. Those peptides with the ability to induce positive selection were all variants of the antigenic peptide and were identified as TCR antagonist peptides for this receptor. One peptide tested, E1, induced positive selection on the beta 2M(-/-) background but negative selection on the beta 2M(+/-) background. These results show that the process of positive selection is exquisitely peptide specific and sensitive to extremely low ligand density and support the notion that low efficacy ligands mediate positive selection.
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            Transforming growth factor-beta regulation of immune responses.

            Transforming growth factor-beta (TGF-beta) is a potent regulatory cytokine with diverse effects on hemopoietic cells. The pivotal function of TGF-beta in the immune system is to maintain tolerance via the regulation of lymphocyte proliferation, differentiation, and survival. In addition, TGF-beta controls the initiation and resolution of inflammatory responses through the regulation of chemotaxis, activation, and survival of lymphocytes, natural killer cells, dendritic cells, macrophages, mast cells, and granulocytes. The regulatory activity of TGF-beta is modulated by the cell differentiation state and by the presence of inflammatory cytokines and costimulatory molecules. Collectively, TGF-beta inhibits the development of immunopathology to self or nonharmful antigens without compromising immune responses to pathogens. This review highlights the findings that have advanced our understanding of TGF-beta in the immune system and in disease.
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              Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis.

               J Yang,  Jie Liu (2001)
              Myofibroblast activation is a key event playing a critical role in the progression of chronic renal disease. Emerging evidence suggests that myofibroblasts can derive from tubular epithelial cells by an epithelial to mesenchymal transition (EMT); however, the details regarding the conversion between these two cell types are poorly understood. Here we dissect the key events during the process of EMT induced by transforming growth factor-beta1. Incubation of human tubular epithelial cells with transforming growth factor-beta1 induced de novo expression of alpha-smooth muscle actin, loss of epithelial marker E-cadherin, transformation of myofibroblastic morphology, and production of interstitial matrix. Time-course studies revealed that loss of E-cadherin was an early event that preceded other alterations during EMT. The transformed cells secreted a large amount of matrix metalloproteinase-2 that specifically degraded tubular basement membrane. They also exhibited an enhanced motility and invasive capacity. These alterations in epithelial phenotypes in vitro were essentially recapitulated in a mouse model of renal fibrosis induced by unilateral ureteral obstruction. Hence, these results indicate that tubular epithelial to myofibroblast transition is an orchestrated, highly regulated process involving four key steps including: 1) loss of epithelial cell adhesion, 2) de novo alpha-smooth muscle actin expression and actin reorganization, 3) disruption of tubular basement membrane, and 4) enhanced cell migration and invasion.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2007
                September 2007
                31 July 2007
                : 107
                : 1
                : e22-e29
                Affiliations
                aInstitute of Physiology and Zürich Center for Integrative Human Physiology, University of Zürich-Irchel, and bClinic for Nephrology, University Hospital Zürich, Zürich, Switzerland
                Article
                106506 Nephron Exp Nephrol 2007;107:e22–e29
                10.1159/000106506
                17671397
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 5, References: 29, Pages: 1
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