Submitted February 4, 2009
Accepted April 10, 2009
Discerning regulation of cis- and trans-presentation of CD8+ T-cell epitopes by EBV-encoded oncogene LMP-1 through self aggregation
Corey Smith, Naohiro Wakisaka, Tania Crough, Jesse Peet, Tomokazu Yoshizaki, Leone Beagley, and Rajiv Khanna*
Australian Centre for Vaccine Development and Tumour Immunology Laboratory, Division of Immunology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
* Corresponding author; email: rajiv.khanna{at}qimr.edu.au.
Activation of the NF-
B pathway by EBV-encoded LMP-1 leads to an up-regulation of the MHC class I antigen processing pathway. Paradoxically, LMP-1 itself induces a subdominant CD8+ T-cell response and appears to have evolved to avoid immune recognition. Here we show that although expression of LMP-1 in human cells dramatically enhanced the trans-presentation of CD8+ T-cell epitopes, cis-presentation of LMP-1 derived epitopes was severely impaired. Testing of a series of LMP-1 mutants revealed that deletion of the first transmembrane domain of LMP-1, which prevented self-aggregation, significantly enhanced cis-presentation of T cell epitopes from this protein, whilst it lost its ability to up-regulate trans-presentation. Interestingly, we also found that cis-presentation of LMP-1 epitopes were rescued by blocking the proteasome function. Taken together, these results delineate a novel mechanism of immune evasion which renders a virally encoded oncogene inaccessible to the conventional MHC class I pathway limiting its cis-presentation to effector cells.
