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

Cytolytic T lymphocyte-associated antigen 4 (CTLA-4) is a critical down-reg ulatory molecule in T cells that plays a major role in peripheral tolerance . Although the CD45 protein tyrosine phosphatase is a potent immunomodulato ry target, the mechanisms by which antibody against CD45RB isoforms (anti-C D45RB) induces allograft tolerance remain unclear. We show here that anti-C D45RB treatment alters CD45 isoform expression on T cells, which is associa ted with rapid up-regulation of CTLA-4 expression. These effects appear spe cific and occur without up-regulation of other activation markers. Administ ration of a blocking monoclonal antibody to CTLA-4 at the time of transplan tation prevents anti CD45RB therapy from prolonging islet allograft surviva l. In addition, treatment with cyclosporin A blocks anti-CD45RB-induced CTL A-4 expression and promotes acute rejection. These data suggest that anti-C D45RB acts through mechanisms that include CTLA-4 up-regulation and demonst rate a link between CD45 and CTLA-4 that depends on calcineurin-mediated si gnaling. They demonstrate also that CTLA-4 expression may be specifically t argeted to enhance allograft acceptance.