A high frequency of naïve PR1-specific CD8+ T cells in umbilical cord blood and fetal thymus suggest incomplete central tolerance to the hematopoietic self-antigen PR1. (46.24)

Abstract

Abstract Tolerance to self-antigens is established primarily in the thymus by negative selection. We have evidence that central tolerance to the HLA-A2 restricted self-peptide, PR1, is incomplete. The frequency of PR1-CTL in umbilical cord blood (UCB) is significantly higher than that seen in the peripheral blood of healthy adults. Investigation in fetal thymic tissue (FT) showed that PR1 is expressed on the surface of thymic dendritic cells (DC) but not thymic epithelial cells. The level of PR1 expression on FT DC is similar to that on UCB DC and healthy adult DC. Comparisons of antigen-specific cells in FT and UCB demonstrated pp65-CTL frequencies were comparable, yet PR1- and WT1-CTL percentages were lower in UCB than in FT. PR1-specific cells, in contrast to pp65- and WT1-specific cells, were found at a higher frequency within CD8 single positive (SP) thymocytes versus CD4+CD8+ double positive (DP) cells, suggesting that PR1-specific SP thymocytes have a survival advantage relative to WT1- and pp65-specific SP thymocytes. In response to PR1 peptide-loaded T2 cells, DP PR1-CTL undergo apoptosis to a greater degree than SP PR1-CTL, implying that higher frequencies of SP PR1-CTL in FT could be due, in part, to a lower susceptibility of SP PR1-CTL to apoptosis. Our data suggest that PR1 expression by DC in the thymus is insufficient for complete central tolerance to PR1 and PR1-specific SP thymocytes may have a survival advantage over other self and viral antigen-specific thymocytes.