title: PolyI:C and mouse survivin artificially embedding human 2B peptide induce a CD4+ T cell response to autologous survivin in HLA-A*2402 transgenic mice.
abstract: CD4(+) T cell effectors are crucial for establishing antitumor immunity. Dendritic cell maturation by immune adjuvants appears to facilitate subset-specific CD4(+) T cell proliferation, but the adjuvant effect for CD4 T on induction of cytotoxic T lymphocytes (CTLs) is largely unknown. Self-antigenic determinants with low avidity are usually CD4 epitopes in mutated proteins with tumor-associated class I-antigens (TAAs). In this study, we made a chimeric version of survivin, a target of human CTLs. The chimeric survivin, where human survivin-2B containing a TAA was embedded in the mouse survivin frame (MmSVN2B), was used to immunize HLA-A-2402/K(b)-transgenic (HLA24(b)-Tg) mice. Subcutaneous administration of MmSVN2B or xenogeneic human survivin (control HsSNV2B) to HLA24(b)-Tg mice failed to induce an immune response without co-administration of an RNA adjuvant polyI:C, which was required for effector induction in vivo. Although HLA-A-2402/K(b) presented the survivin-2B peptide in C57BL/6 mice, 2B-specific tetramer assays showed that no CD8(+) T CTLs specific to survivin-2B proliferated above the detection limit in immunized mice, even with polyI:C treatment. However, the CD4(+) T cell response, as monitored by IFN-γ, was significantly increased in mice given polyI:C+MmSVN2B. The Th1 response and antibody production were enhanced in the mice with polyI:C. The CD4 epitope responsible for effector function was not Hs/MmSNV13-27, a nonconserved region between human and mouse survivin, but region 53-67, which was identical between human and mouse survivin. These results suggest that activated, self-reactive CD4(+) helper T cells proliferate in MmSVN2B+polyI:C immunization and contribute to Th1 polarization followed by antibody production, but hardly participate in CTL induction.
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kasamatsu
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan; Department of Hematology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan.
authors.forename: Shojiro
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Azuma
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Morii-Sakai
authors.affiliation: Department of Hematology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Imamura
authors.affiliation: Department of Hematology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Teshima
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Chuoh-ku, Sapporo, Japan.
authors.forename: Akari
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Chuoh-ku, Sapporo, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirohashi
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Chuoh-ku, Sapporo, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Chuoh-ku, Sapporo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan. Electronic address: seya-tu@pop.med.hokudai.ac.jp.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005091:Exons; D015870:Gene Expression; D023061:Gene Order; D056426:Genetic Loci; D059871:HLA-A24 Antigen / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D011070:Poly I-C / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; D018984:Epitopes, T-Lymphocyte; C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; D051034:Inhibitor of Apoptosis Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000077022:Survivin; D011070:Poly I-C
keywords: CD4 epitope; Interferon-γ; Peptide vaccine; PolyI:C; Survivin; Th1 response; Tumor immunity