Cytotoxic T Lymphocyte Escape Variants, Induced Mutations, and Synthetic Peptides Define a Dominant H-2Kb-Restricted Determinant in Simian Virus 40 Tumor Antigen

Roberts

et al. 2000

J Virol

Self Cite

137

The cytotoxic T-lymphocyte response to wild-type simian virus 40 large tumor antigen (Tag) in C57BL/6 (H2 b ) mice is directed against three H2-D b -restricted epitopes, I, II/III, and V, and one H2-K b -restricted epitope, IV. Epitopes I, II/III, and IV are immunodominant, while epitope V is immunorecessive. We investigated whether this hierarchical response was established in vivo or was due to differential expansion in vitro by using direct enumeration of CD8 ؉ T lymphocytes with Tag epitope/major histocompatibility complex class I tetramers and intracellular gamma interferon staining. The results demonstrate that epitope IV-specific CD8 ؉ T cells dominated the Tag-specific response in vivo following immunization with full-length Tag while CD8 ؉ T cells specific for epitopes I and II/III were detected at less than one-third of this level. The immunorecessive nature of epitope V was apparent in vivo, since epitope V-specific CD8 ؉ T cells were undetectable following immunization with full-length Tag. In contrast, high levels of epitope V-specific CD8 ؉ T lymphocytes were recruited in vivo following immunization and boosting with a Tag variant in which epitopes I, II/III, and IV had been inactivated. In addition, analysis of the T-cell receptor ␤ (TCR␤) repertoire of Tag epitope-specific CD8 ؉ cells revealed that multiple TCR␤ variable regions were utilized for each epitope except Tag epitope II/III, which was limited to TCR␤10 usage. These results indicate that the hierarchy of Tag epitope-specific CD8 ؉ T-cell responses is established in vivo.Immunity to the large tumor antigen (Tag) of simian virus 40 (SV40) in C57BL/6 mice is characterized by the development of CD8 (23,34,50,52). An immunological hierarchy has been demonstrated among these four epitopes within Tag. Immunization of C57BL/6 mice with SV40, SV40 Tagtransformed cells, or a recombinant vaccinia virus (rVV) which encodes the full-length Tag leads to the induction of cytotoxic T lymphocytes (CTL) specific for epitopes I, II/III, and IV (26, 41, 51). Frequency estimates from limiting-dilution analysis of splenic lymphocytes obtained 9 days after immunization with SV40 Tag-transformed cells revealed that epitope IV-specific CTL represent 1 in 14,000 splenocytes while epitope I and II/III-specific CTL were less abundant (1 in 67,000) and epitope V-specific CTL were undetectable (41).Although epitope V-specific CTL are not detected following immunization with full-length SV40 Tag, immunization with syngeneic cells carrying inactivating mutations or deletions in Tag epitopes I, II/III, and IV leads to the induction of epitope V-specific CTL (41, 50). Accordingly, epitope V has been characterized as immunorecessive. Additional strategies which enhance the immunogenicity of epitope V include immunization with rVVs which express epitope V as a minigene linked to a secretory signal sequence (ES) or in which the epitope V sequence is inserted into a nonimmunogenic murine self protein, dihydrofolate reductase (26). Precise mechanisms which control the immun...

Section: Animals Male or Female C57bl/6 (H-2mentioning

confidence: 99%

“…Four distinct H2 b -restricted CD8 ϩ T-lymphocyte epitopes, epitopes I, II/III, IV, and V, have been identified and precisely mapped within SV40 Tag. Epitope IV, Tag residues 404 to 411, is H2-K b restricted (42,52). Epitopes I (residues 206 to 215), II/III (residues 223 to 231), and V (residues 489 to 497) are restricted by H2-D b (23,34,50,52).…”

mentioning

confidence: 99%

Quantitation of CD8⁺T-Lymphocyte Responses to Multiple Epitopes from Simian Virus 40 (SV40) Large T Antigen in C57BL/6 Mice Immunized with SV40, SV40 T-Antigen-Transformed Cells, or Vaccinia Virus Recombinants Expressing Full-Length T Antigen or Epitope Minigenes

Mylin

Roberts

et al. 2000

J Virol

Self Cite

137

“…In C57BL/6 mice, immunization with full-length Tag results in a hierarchical response to multiple CTL epitopes (10,11). Four CTL epitopes have been defined, including epitope I, Tag residues 206 -215; epitope II/III, Tag residues 223-231; epitope IV, Tag residues 404 -411; and epitope V, Tag residues 489 -497 (12)(13)(14)(15)(16). Epitopes I, II/III, and V are H2-D b restricted, and epitope IV is H2-K b restricted.…”

Section: Control Of Advanced Choroid Plexus Tumors In Sv40 T Antigen mentioning

confidence: 99%

Control of Advanced Choroid Plexus Tumors in SV40 T Antigen Transgenic Mice Following Priming of Donor CD8+ T Lymphocytes by the Endogenous Tumor Antigen

The Journal of Immunology

Tevethia

2001

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Mouse models in which tumors arise spontaneously due to the transgenic expression of an oncoprotein provide an opportunity to test approaches that target the immune-mediated control of tumor progression. In this report we investigated the role of SV40 Tag-specific CD8+ T cells in the control of advanced choroid plexus tumor progression using large tumor Ag (Tag) transgenic mice. Since mice of the SV11 line are tolerant to the immunodominant SV40 Tag-derived CTL epitopes, mice with advanced stage tumors were reconstituted with naive C57BL/6 spleen cells following a low dose of γ-irradiation. This led to the priming of CTLs specific for the H2-Kb-restricted epitope IV by the endogenous Tag and a significant increase in the life span of Tag transgenic mice. Epitope IV-specific CD8+ T cells accumulated and persisted in the brains and tumors of SV11 mice, as determined by analysis with epitope-specific MHC class I tetramers. Brain-infiltrating epitope IV-specific T cells were capable of producing IFN-γ as well as lysing syngeneic Tag-transformed cells in vitro. In addition, the adoptive transfer of spleen cells from Tag-immune C57BL/6 mice resulted in a dramatic increase in the control of tumor progression in SV11 mice and was associated with the accumulation of CD8+ T cells specific for multiple Tag epitopes in the brain. These results indicate that the control of advanced stage spontaneous choroid plexus tumors is associated with the induction of a strong and persistent CD8+ T cell response to Tag.

“…Epitopes I (residues 206 -215), II/III (residues 223-231), and V (residues 489 -497) are H-2D b (Db)-restricted, whereas epitope IV (residues 404 -411) is H-2K b (Kb)-restricted. These four T Ag-derived, T CD8 -recognized epitopes fall on a hierarchical scale, with epitope IV being the most immunodominant followed by epitopes I and II/III (27,28). Epitope V is immunorecessive and not immunogenic unless the three dominant epitopes are inactivated in T Ag (29,30).…”

mentioning

confidence: 99%

Early Immunization Induces Persistent Tumor-Infiltrating CD8+ T Cells against an Immunodominant Epitope and Promotes Lifelong Control of Pancreatic Tumor Progression in SV40 Tumor Antigen Transgenic Mice

Otáhal

The Journal of Immunology

Hutchinson

et al. 2006

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The ability to recruit the host’s CD8+ T lymphocytes (TCD8) against cancer is often limited by the development of peripheral tolerance toward the dominant tumor-associated Ags. Because multiple epitopes derived from a given tumor Ag (T Ag) can be targeted by TCD8, vaccine approaches should be directed toward those TCD8 that are more likely to survive under conditions of persistent Ag expression. In this study, we investigated the effect of peripheral tolerance on the endogenous TCD8 response toward two epitopes, designated epitopes I and IV, from the SV40 large T Ag. Using rat insulin promoter (RIP) 1-Tag4 transgenic mice that express T Ag from the RIP and develop pancreatic insulinomas, we demonstrate that epitope IV- but not epitope I-specific TCD8 are maintained long term in tumor-bearing RIP1-Tag4 mice. Even large numbers of TCR-transgenic T cells specific for epitope I were rapidly eliminated from RIP1-Tag4 mice after adoptive transfer and recognition of the endogenous T Ag. Importantly, immunization of RIP1-Tag4 mice at 5 wk of age against epitope IV resulted in complete protection from tumor progression over a 2-year period despite continued expression of T Ag in the pancreas. This extensive control of tumor progression was associated with the persistence of functional epitope IV-specific TCD8 within the pancreas for the lifetime of the mice without the development of diabetes. This study indicates that an equilibrium is reached in which immune surveillance for spontaneous cancer can be achieved for the lifespan of the host while maintaining normal organ function.