Cytotoxic class I tetramers inhibit CTL priming and alter immunodominance hierarchies in the HY model system (145.33)

Abstract

Abstract The CD8+ cytotoxic T lymphocyte (CTL) response is a major effector mechanism in allograft rejection. In this study, we used the well-established murine HY-reactive immune response as a rejection model. Sensitization of B6 females with male bone marrow generated robust Db-Uty and Db-Smcy tetramer-positive CTLs that produced IFN-gamma, TNF-alpha, and granzyme B. We hypothesized that treatment of female mice with Db-Uty or Db-Smcy tetramers coupled to the ribosome-inactivating toxin, saporin, would selectively delete naïve cognate T cells and prevent priming of CTL responses. As expected, administration of the cytotoxic tetramers prior to immunization dramatically reduced the HY -specific CTL population at the peak of expansion and permitted the survival of adoptively-transferred, HY peptide-pulsed female cells. Interestingly, elimination of one CTL population magnified T cell reactivity against the remaining dominant epitope, demonstrating that the relative amplitude of these responses depends, in part, on competition between CD8+ T cells during priming. These data suggest that cytotoxic class I tetramers could be useful to dissect or manipulate T cell immunodominance hierarchies.