An Endoplasmic Reticulum-Targeting Signal Sequence Enhances the Immunogenicity of an Immunorecessive Simian Virus 40 Large T Antigen Cytotoxic T-Lymphocyte Epitope

Autor: Todd D. Schell, Tong-Ming Fu, Lawrence M. Mylin, Igor Bacik, Satvir S. Tevethia, Jack R. Bennink, Gustav Russ, Jonathan W. Yewdell
Rok vydání: 1998
Předmět:
Zdroj: Journal of Virology. 72:1469-1481
ISSN: 1098-5514
0022-538X
DOI: 10.1128/jvi.72.2.1469-1481.1998
Popis: Cells infected with viruses or undergoing oncogenic transformation express new or altered self-proteins that may trigger host immune responses. CD8+ cytotoxic T lymphocytes (CTL) recognize such proteins in the form of small antigenic peptide fragments complexed with cell surface major histocompatibility complex (MHC) class I molecules (32, 86). Peptides presented by MHC class I complexes are generated largely from endogenously synthesized proteins through proteolysis in the cytosol, often by the action of proteasomes (22, 47, 63, 80), and are delivered to the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP) (49, 83, 87), where they are assembled with nascent class I molecules. The resulting complex is then transported via the secretory pathway to the cell surface (17, 55, 81, 85). Multiple factors contribute to the ability of a given determinant in a protein to elicit a CTL response. These include the efficiency of production of the peptide and transport to the ER (7, 8, 20, 26, 54, 57), peptide affinity for class I molecules (15, 82), and the frequency of potentially reactive T cells in the repertoire (12, 18, 52, 56). We have used simian virus 40 (SV40) large tumor, or T, antigen (SV40 Tag) to understand factors which govern the immunogenicity of CTL determinants within a tumor antigen. SV40 Tag is a multifunctional 94-kDa nuclear oncoprotein which can initiate and maintain transformation of a wide variety of cell types in vitro (28). In vivo, the Tag can induce neoplasia with a metastatic potential when expressed as a transgene under control of a tissue-specific promoter or when expressed from the viral promoter (10, 34, 37, 59). In the immunocompetent host, the Tag often induces a vigorous cellular immune response which leads to the rejection of transplanted Tag-induced tumors (reviewed in references 76 and 77). Although SV40 Tag has long served as a model tumor inducer and immunogen in experimental systems, more recent detection of SV40 virus in isolates derived from human tumors has prompted renewed interest in the potential role of the immune system in controlling tumor induction by SV40 (9, 13, 41, 46). SV40 Tag contains four H-2b-restricted CTL determinants, of which three are H-2Db restricted (19, 43, 51, 77). These include CTL determinants I (residues 206 to 215), II/III (residues 223 to 231), and determinant V (residues 489 to 497). Determinant V was previously characterized as immunorecessive within the context of the full-length Tag (50, 69). That is, determinant V-specific CTL responses were detected only (and then with some difficulty) following immunization of mice with transformed cells expressing a mutated Tag in which the three immunodominant determinants (determinants I, II/III, and IV) were deleted or rendered nonantigenic (50, 69). To further characterize the immunological potential of the H-2b-restricted SV40 Tag CTL epitopes, including the immunorecessive determinant V, we have extended these findings by examining the antigenicity and immunogenicity of SV40 Tag CTL determinants expressed in various polypeptide contexts from recombinant vaccinia viruses (rVVs). Our results show that the immunogenicity of the immunorecessive epitope V is significantly enhanced by targeting it to the ER.
Databáze: OpenAIRE
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