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¹ Australian Centre for Vaccine Development and Tumour Immunology Laboratory, Division of Infectious Diseases and Immunology, Clive Berghofer Cancer Research Centre, Queensland Institute of Medical Research, Brisbane (Qld) 4006, Australia
² Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

CORRESPONDENCE Rajiv Khanna: rajivK{at}qimr.edu.au OR Judy Tellam: judyT{at}qimr.edu.au

A significant proportion of endogenously processed CD8⁺ T cell epitopes are derived from newly synthesized proteins and rapidly degrading polypeptides (RDPs). It has been hypothesized that the generation of rapidly degrading polypeptides and CD8⁺ T cell epitopes from these RDP precursors may be influenced by the efficiency of protein translation. Here we address this hypothesis by using the Epstein-Barr virus–encoded nuclear antigen 1 protein (EBNA1), with or without its internal glycine-alanine repeat sequence (EBNA1 and EBNA1GA, respectively), which display distinct differences in translation efficiency. We demonstrate that RDPs constitute a significant proportion of newly synthesized EBNA1 and EBNA1GA and that the levels of RDPs produced by each of these proteins directly correlate with the translation efficiency of either EBNA1 or EBNA1GA. As a consequence, a higher number of major histocompatibility complex–peptide complexes can be detected on the surface of cells expressing EBNA1GA, and these cells are more efficiently recognized by virus-specific cytotoxic T lymphocytes compared to the full-length EBNA1. More importantly, we also demonstrate that the endogenous processing of these CD8⁺ T cell epitopes is predominantly determined by the rate at which the RDPs are generated rather than the intracellular turnover of these proteins.

J. Tellam and M.H. Fogg contributed equally to this work.

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