N‐terminal trimer extension of nominal CD8 T cell epitopes is sufficient to promote cross‐presentation to cognate CD8 T cells in vivo

Abstract

Cross‐presentation pathway is essential for generating effective CD8 T cell responses against cell‐associated antigens derived from either infectious pathogens or malignant cells. In this study, we investigated the regulation of cross‐presentation pathway through manipulation of the CD8 T cell epitopes using TCR transgenic mice as model system. Previous studies have shown that nominal peptide is inefficiently cross‐presented and that proteins and large polypeptides that require proteasomal processing are the main source of naturally cross‐presented antigens. Here we show that N‐terminal extension of nominal peptide by as few as three residues is sufficient to produce a substrate for TAP dependent cross‐presentation that is highly efficient in cross‐priming murine CD8 T cells in vivo. On a molar basis, cross‐priming with trimer extended peptide is 20 fold more efficient than priming with intact protein. Depending on the presence or absence of inflammatory signals, this method can lead to immunity or tolerance. Moreover, cross‐presentation of N‐terminal modified CD8 epitopes derived from insulin can significantly protect NOD mice from developing type I diabetes. Therefore, this method of peptide extension should prove of great value in facilitating in vivo studies of CD8 immunity and tolerance that rely on cross‐presentation.(This work was supported by NIH grants DK50824 and U19 AI050864)