PolyI:C and mouse survivin artificially embedding human 2B peptide induce a CD4+ T cell response to autologous survivin in HLA-A2402 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/Kb -transgenic (HLA24b -Tg) mice. Subcutaneous administration of MmSVN2B or xenogeneic human survivin (control HsSNV2B) to HLA24b -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/Kb 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.