An Alternative Open Reading Frame of the Human Macrophage Colony-stimulating Factor Gene Is Independently Translated and Codes for an Antigenic Peptide of 14 Amino Acids Recognized by Tumor-infiltrating CD8 T Lymphocytes

doi:10.1084/jem.193.10.1189

Published online 21 May 2001.

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© The Rockefeller University Press, 0022-1007/2001/5/1189/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 10, May 21, 2001 1189-1198

Original Article

An Alternative Open Reading Frame of the Human Macrophage Colony-stimulating Factor Gene Is Independently Translated and Codes for an Antigenic Peptide of 14 Amino Acids Recognized by Tumor-infiltrating CD8 T Lymphocytes

Michael Probst-Kepper^a,c, Vincent Stroobant^a, Robert Kridel^a, Béatrice Gaugler^a, Claire Landry^a, Francis Brasseur^a, Jean-Pierre Cosyns^b, Birgit Weynand^b, Thierry Boon^a, and Benoit J. Van den Eynde^a
^a Ludwig Institute for Cancer Research and Cellular Genetics Unit, Université Catholique de Louvain, Brussels 1200, Belgium
^b Department of Pathology, Université Catholique de Louvain, Brussels 1200, Belgium
^c Molecular Immunology Group, German Research Centre for Biotechnology, Braunschweig 38124, Germany

Correspondence to: Benoit J. Van den Eynde, Ludwig Institute for Cancer Research and Cellular Genetics Unit, Université Catholique de Louvain 7459, Ave. Hippocrate 74, B-1200 Brussels, Belgium. Tel:32-2-764-7572 Fax:32-2-764-7590 E-mail:benoit.vandeneynde{at}bru.licr.org.

We show that cytotoxic T lymphocytes (CTLs) infiltrating a kidneytumor recognize a peptide encoded by an alternative open readingframe (ORF) of the macrophage colony-stimulating factor (M-CSF)gene. Remarkably, this alternative ORF, which is translatedin many tumors concurrently with the major ORF, is also translatedin some tissues that do not produce M-CSF, such as liver andkidney. Such a dissociation of the translation of two overlappingORFs from the same gene is unexpected. The antigenic peptideencoded by the alternative ORF is presented by human histocompatibilityleukocyte antigen (HLA)-B*3501 and has a length of 14 residues.Peptide elution indicated that tumor cells naturally presentthis 14 mer, which is the longest peptide known to be recognizedby CTLs. Binding studies of peptide analogues suggest that itbinds by its two extremities and bulges out of the HLA grooveto compensate for its length.

Key Words: renal cell carcinoma, HLA-B35, translation, peptide binding,natural peptide

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