Abstract
Cytolytic T lymphocyte–associated antigen 4 (CTLA-4) is a critical down-regulatory molecule in T cells that plays a major role in peripheral tolerance. Although the CD45 protein tyrosine phosphatase is a potent immunomodulatory target, the mechanisms by which antibody against CD45RB isoforms (anti-CD45RB) induces allograft tolerance remain unclear. We show here that anti-CD45RB treatment alters CD45 isoform expression on T cells, which is associated with rapid up-regulation of CTLA-4 expression. These effects appear specific and occur without up-regulation of other activation markers. Administration of a blocking monoclonal antibody to CTLA-4 at the time of transplantation prevents anti-CD45RB therapy from prolonging islet allograft survival. In addition, treatment with cyclosporin A blocks anti-CD45RB–induced CTLA-4 expression and promotes acute rejection. These data suggest that anti-CD45RB acts through mechanisms that include CTLA-4 up-regulation and demonstrate a link between CD45 and CTLA-4 that depends on calcineurin-mediated signaling. They demonstrate also that CTLA-4 expression may be specifically targeted to enhance allograft acceptance.
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Acknowledgements
Supported in part by the NIH (grants AI-36317 and AI-45485 to D. M. R. and AI-41521 to M. H. S.) and the Juvenile Diabetes Foundation International (G. P. B. and S. F.). We thank J. Allison for the gift of reagents and K. Bottomly, D. Metz, J. Madreans and Z. Yin for helpful discussions.
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Fecteau, S., Basadonna, G., Freitas, A. et al. CTLA-4 up-regulation plays a role in tolerance mediated by CD45. Nat Immunol 2, 58–63 (2001). https://doi.org/10.1038/83175
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DOI: https://doi.org/10.1038/83175
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