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CTLA-4 up-regulation plays a role in tolerance mediated by CD45

Nature Immunology volume 2, pages 58–63 (2001)Cite this article

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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Figure 1: Anti–CTLA-4 does not alter the anti-CD45RB–mediated shift in CD45 isoforms.
Figure 2: CTLA-4 expression is up-regulated by anti-CD45RB treatment.
Figure 3: Time course of the shift in CD45 isoforms and CTLA-4 induction after anti-CD45RB treatment.
Figure 4: Anti-CD45RB treatment does not induce expression of other activation markers.
Figure 5: CsA blocks the anti-CD45RB–mediated increase in CTLA-4 expression on CD4 cells and inhibits prolongation of allograft survival.

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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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Author notes

  1. Scott Fecteau and Giacomo P. Basadonna: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Yale Medical School, New Haven, 06520, CT, USA

    Scott Fecteau, Giacomo P. Basadonna, Alexander Freitas & Charlotte Ariyan

  2. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, MA, USA

    Mohamed H. Sayegh

  3. Department of Internal Medicine, Yale Medical School, New Haven, 06520, CT, USA

    David M. Rothstein

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Correspondence to David M. Rothstein.

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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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