Epitopes derived by incidental translational frameshifting give rise to a protective CTL response.
Aberrant gene expression can be caused by several different mechanisms at the transcriptional, RNA processing, and translational level. Although most of the resulting proteins may have no significant biological function, they can be meaningful for the immune system, which is sensitive to extremely low levels of Ag. We have tested this possibility by investigating the ability of CD8+ T cells (TCD8+) to respond to an epitope whose expression results from incidental ribosomal frameshifting at a sequence element within the HSV thymidine kinase gene. This element, with no apparent functional significance, has been identified due to its ability to facilitate escape from the antiviral compound acyclovir. Using a recombinant vaccinia virus expression system, we find that in vitro and in vivo TCD8+ responses to the frameshift-dependent epitope are easily discernible. Furthermore, the in vivo response is at a sufficient level to mediate protection from a tumor challenge. Thus, the targets of immune responses to infectious agents can extend beyond the products of conventional open reading frames. On a per-cell basis, responses to such minimally expressed epitopes may be exceedingly effective due to the selective expansion of high avidity TCD8+.
Zook
Matthew B
MB
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Howard
Michael T
MT
Sinnathamby
Gomathinayagam
G
Atkins
John F
JF
Eisenlohr
Laurence C
LC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D004527:Egg Proteins / Q000235:genetics / Q000502:physiology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000502:physiology; D005260:Female; D018965:Frameshifting, Ribosomal; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008223:Lymphoma / Q000276:immunology / Q000821:virology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation / Q000276:immunology; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000235:genetics / Q000502:physiology; D010047:Ovalbumin / Q000235:genetics / Q000502:physiology; D010446:Peptide Fragments; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D013937:Thymidine Kinase / Q000235:genetics / Q000502:physiology; D014758:Viral Core Proteins / Q000235:genetics / Q000502:physiology
D000911:Antibodies, Monoclonal; D004527:Egg Proteins; D018984:Epitopes, T-Lymphocyte; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; C110366:OVA-8; D010446:Peptide Fragments; D016601:RNA-Binding Proteins; D011948:Receptors, Antigen, T-Cell; D014758:Viral Core Proteins; D010047:Ovalbumin; D013937:Thymidine Kinase