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      B7-1 (CD80) and B7-2 (CD 86) Expression in Human Tubular Epithelial Cells in vivo and in vitro<footref rid="foot01"> 1</footref>

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          Abstract

          Background: Tubulointerstitial inflammation with infiltration of mononuclear cells plays an important role in acute allograft rejection and in the progression of renal diseases. We therefore investigated in vivo the expression of the costimulatory molecules B7-1 and B7-2 on proximal tubular epithelial cells (PTEC) under normal and pathologic conditions and analyzed the regulation and functional role of these molecules after cytokine and CD40 activation in vitro. Methods: Immunohistological staining for B7-1 and B7-2 on cryostat sections of core needle biopsies from patients with different renal diseases was examined. Patients were divided into three groups: group A: diffuse interstitial inflammation; group B: minor interstitial inflammation; group C: no interstitial inflammation. In addition, the expression of B7-1 and B7-2 protein and mRNA of cultured PTEC that had been stimulated with cytokine-combinations in absence or presence of a stimulatory anti-CD40 antibody was investigated by means of FACS analysis and RT-PCR. The functional role was analyzed in MKLCs with cytokine and anti-CD40 prestimulated PTEC by measuring IFN-γ and IL-2 expression in absence or presence of CTLA4-Ig by ELISA. Results: Group A patients showed intense tubular staining for B7-1 and B7-2, group B patients showed mild staining, whereas in group C patients B7-1 and B7-2 staining was negative or only weakly positive. In vitro, the presence of B7-1 and B7-2 on PTEC was increased after stimulation with combinations of IL-1α, IL-4, IFN-γ or IL-13 instead of IL-4 and CD40 activation. B7-1 and B7-2 mRNA could be detected in PTEC as well. In MKLCs only cytokine and anti-CD40 prestimulated PTEC were able to stimulate IFN-γ and IL-2 production by purified T cells, which could be blocked dose-dependently by CTLA4-Ig. Conclusion: This study clearly shows that B7-1 and B7-2 can be induced on PTEC in vivo and in vitro. After B7-1 and B7-2 induction, PTEC costimulate CD28 on T lymphocytes resulting in cytokine production. This might be of relevance in allograft rejection and in various kidney diseases.

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          T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions.

          Although in vivo priming of CD8+ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4+ T-helper lymphocytes, the nature of the 'help' provided to CTLs is unknown. One widely held view is that help for CTLs is mediated by cytokines produced by T-helper cells activated in proximity to the CTL precursor at the surface of an antigen-presenting cell (APC). An alternative theory is that, rather than being directly supplied to the CTL by the helper cell, help is delivered through activation of the APC, which can then prime the CTL directly. CD40 and its ligand, CD40L, may activate the APC to allow CTL priming. CD40L is expressed on the surface of activated CD4+ T-helper cells and is involved in their activation and in the development of their effector functions. Ligation of CD40 on the surface of APCs such as dendritic cells, macrophages and B cells greatly increases their antigen-presentation and co-stimulatory capacity. Here we report that signalling through CD40 can replace CD4+ T-helper cells in priming of helper-dependent CD8+ CTL responses. Blockade of CD40L inhibits CTL priming; this inhibition is overcome by signalling through CD40. CD40-CD40L interactions are therefore vital in the delivery of T-cell help for CTL priming.
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            A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell.

            To generate an immune response, antigen-specific T-helper and T-killer cells must find each other and, because they cannot detect each other's presence, they are brought together by an antigen-loaded dendritic cell that displays antigens to both. This three-cell interaction, however, seems nearly impossible because all three cell types are rare and migratory. Here we provide a potential solution to this conundrum. We found that the three cells need not meet simultaneously but that the helper cell can first engage and 'condition' the dendritic cell, which then becomes empowered to stimulate a killer cell. The first step (help) can be bypassed by modulation of the surface molecule CD40, or by viral infection of dendritic cells. These results may explain the long-standing paradoxical observation that responses to some viruses are helper-independent, and they evoke the possibility that dendritic cells may take on different functions in response to different conditioning signals.
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              Costimulatory function and expression of CD40 ligand, CD80, and CD86 in vascularized murine cardiac allograft rejection.

              Recent data implicates a role for the CD40-CD40 ligand (CD40L) pathway in graft rejection. One potential mechanism is direct costimulation of T cells through CD40L. Alternatively, the ability of CD40 stimulation to induce CD80 (B7-1) and CD86 (B7-2) expression on antigen-presenting cells (APCs) has led to the hypothesis that the role of CD40-CD40L interactions in transplant rejection might be indirect, i.e., to promote the costimulatory capacity of APCs. Here, we have used a murine vascularized cardiac allograft model to test this hypothesis. Treatment of the recipients with donor splenocytes and a single dose of anti-CD40L mAb induces long-term graft survival (> 100 days) in all animals. This is associated with marked inhibition of intragraft Th1 cytokine [interferon gamma and interleukin (IL) 2] and IL-12 expression with reciprocal up-regulation of Th2 cytokines (IL-4 and IL-10). In untreated allograft recipients, CD86 is strongly expressed on endothelial cells and infiltrating mononuclear cells of the graft within 24 hr. In contrast, CD80 expression is not seen until 72 hr after engraftment. Anti-CD40L mAb has no detectable effect on CD86 up-regulation, but almost completely abolishes induction of CD80. However, animals treated with anti-CD80 mAb or with a mutated form of CTLA4Ig (which does not bind to CD86) rejected their cardiac allografts, indicating that blockade of CD80 alone does not mediate the graft-prolonging effects of anti-CD40L mAb. These data support the notion that the role of CD40-CD40L in transplant rejection is not solely to promote CD80 or CD86 expression, but rather that this pathway can directly and independently costimulate T cells. These data also suggest that long-term graft survival can be achieved without blockade of either T cell receptor-mediated signals or CD28-CD86 engagement.
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2002
                September 2002
                26 September 2002
                : 92
                : 3
                : 542-556
                Affiliations
                aVth Medical Clinic, Klinikum Mannheim, Ruprecht-Karls University of Heidelberg at Mannheim, and bInstitute of Pathology, Heidelberg, Germany
                Article
                64084 Nephron 2002;92:542–556
                10.1159/000064084
                12372936
                © 2002 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: 10, Tables: 2, References: 60, Pages: 15
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/64084
                Categories
                Original Paper

                Cardiovascular Medicine, Nephrology

                Proximal tubular epithelial cells, CD40, B7-2, B7-1, Human

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