Conditional expression of tissue-specific antigen regulates CD8 T cell tolerance induction (101.3)

Abstract

We have developed a carefully-designed transgenic model to learn how expression of an autoantigen influences the degree and nature of tolerance. The surrogate antigen, directed to thyroid by a tissue-specific promoter, consists of a cell-surface glycoprotein (human interleukin-2 receptor α chain, Tac) to which well-defined B cell, CD8+ T cell, and CD4+ T cell epitopes have been appended in order to assess all three lymphocyte subset responses. A LoxP-flanked stop cassette was inserted between the tissue-specific promoter and the transgene open reading frame (ORF) to allow for conditional expression. To avoid positional and copy number effects in traditional transgenesis, the transgene was targeted to HPRT locus with a single-copy insertion. Here we show that embryonic but not adult expression of Tac transgene results in a profound epitope-specific CD8 T cell tolerance. However, prolonged expression of postnatal antigen is able to facilitate tolerance induction. Moreover, the ability to induce Tac-specific immune tolerance correlates with the loss of susceptibility to rejection of Tac-expressing tumor cells. These findings provide direct evidence of dynamic tolerance induction to normal or tumor antigens.