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© The Rockefeller University Press, 0022-1007/1997/10/1051/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 7, October 6, 1997 1051-1058

Articles

Initiation Codon Scanthrough versus Termination Codon Readthrough Demonstrates Strong Potential for Major Histocompatibility Complex Class I–restricted Cryptic Epitope Expression

Timothy N.J. Bullock, Anthony E. Patterson, Laura L. Franlin, Evangelia Notidis, and Laurence C. Eisenlohr

From the Department of Microbiology and Immunology, Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107

Accumulating evidence shows that the repertoire of major histocompatibility complex class I–restricted epitopes extends beyond conventional translation reading frames. Previously, we reported that scanthrough translation, where the initiating AUG of a primary open reading frame is bypassed, is most likely to account for the presentation of cryptic epitopes from alternative reading frames within the influenza A PR/8/34 nucleoprotein gene. Here, we confirm and extend these findings using an epitope cassette construct that features two well-defined CD8+ T cell (TCD8+) epitopes in alternative reading frames, each preceded by a single start codon. Expression of one epitope depends on scanning of the ribosome over the first AUG with translation initiation occurring at the second AUG. We find that scanthrough translation has great potency in our system, with its impact being modulated, as predicted, by the base composition surrounding the first initiation codon, the number of start codons preceding the point of alternate reading frame initiation, and the efficiency with which the epitope itself is generated. Additionally, we investigated the efficiency of eukaryotic translation termination codons, to assess codon readthrough as a mechanism for cryptic epitope expression from 3' untranslated regions. In contrast with initiation codons, eukaryotic stop codons appear to be highly efficient at preventing expression of epitopes encoded in 3' untranslated regions, suggesting that 3' untranslated regions are not a common source of cryptic epitope substrate. We conclude that scanthrough is a powerful mechanism for the expression of epitopes encoded in upstream alternative open reading frames that may contribute significantly to TCD8+ responses and to tolerance induction.

Address correspondence to L.C. Eisenlohr, Thomas Jefferson University, BLSB Rm 726, 233 South 10th St., Philadelphia, PA 19107. Phone: 215-503-4540; FAX: 215-923-4153; E-mail: L_Eisenlohr{at}lac.jci.tju.edu. The current address for T.N.J. Bullock is Beirne Carter Center for Immunology Research, Health Sciences Center, Box 4012, University of Virginia, Charlottesville, VA 22908. The current address for L.N. Franlin is Merck & Co., Inc., Merck Research Laboratories, Laura Franlin WP26A-3000, West Point, PA 19486.

L.C. Eisenlohr is supported by the American Cancer Society (RPG-94-008-03-IM) and the National Institutes of Health (RO1-AI36331).

1 Abbreviations used in this paper: NP, nucleoprotein; nt, nucleotide; ORF, open reading frame; RF, reading frame; TCD8+, CD8+ T cell; UTR, untranslated region; vac, vaccinia virus.


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