Dissecting the mechanisms of CD8+ T cell tolerance to the proto-oncogene HER-2/NEU in the HER-2/NEU transgenic mouse model of mammary cancer

The HER-2/neu (neu-N) transgenic mice are a clinically relevant model of breast cancer. They are derived from the parental FVB/N mouse strain and are transgenic for the rat form of the proto-oncogene HER-2/neu (neu). Previously published studies have shown that neu-N mice demonstrate immune tolerance to their endogenous neu protein in both the humoral and cellular compartments. The aim of this thesis was to understand the mechanism of CD8+ T cell tolerance in neu-N mice. We first identified a MHC I peptide in the neu protein that is recognized by CD8+ T cells derived from vaccinated FVB/N mice. This 10-mer (RNEU_420–429) was recognized by all tumor-specific FVB/N-derived T cells generated regardless of the TCR Vβ region expressed by the T cell or the method of vaccination employed, establishing it as the immunodominant MHC I epitope in rat neu. While vaccinated FVB/N mice will develop T cells specific for the immundominant epitope, the majority of neu-N mice develop T cells specific for an as yet unidentified, presumably less immunogenic cryptic epitope in neu. Three CD8+ T cell lines derived from both vaccinated FVB/N and neu-N mice specific for RNEU_420–429 were compared using a peptide/MHC tetramer. It was found that RNEU_420–429-specific T cells from vaccinated neu-N mice exhibit lower avidity than T cells isolated from parental nontolerized mice. However, high avidity RNEU_420–429-specific T cells could be recovered in neu-N mice receiving immune modulating doses of chemotherapy. Furthermore, induction of high avidity RNEU _420–429-specific T cells correlates with the mouse's ability to reject transplanted neu-expressing tumors. Therefore, peripheral tolerance mechanisms in neu-N mice effect at a minimum high-avidity T cells specific for the immunodominant epitope. Importantly, proper vaccination regimen can overcome this tolerance and produce more effective antitumor immunity.