T and B Cell Immune Responses to Tumor Antigen MUC1 are Induced by Targeting Antigen to B Lymphocytes (50.20)

Abstract

Abstract To test the hypothesis that MUC1 specific T cell responses may be induced by targeting MUC1 to B cells in the presence of CpG ODN adjuvant, we first conjugated a model Ag ovalbumin (OVA) with anti-CD19 mAb as a means to target Ag to B cells. OVA TCR transgenic CD8 T cells (OT-I) and CD4 T cells (OT-II) were used to exam if targeting OVA to B cells through CD19 leads to Ag presentation in the context of MHC class I and II for T cell activation. The results indicated that OVA conjugates could significantly induce CD4 and CD8 T cells proliferation and activation. These expanded T cells were not deleted or anergized, and were characterized by proliferation (OT-II T cells) and IFN-γ release (OT-I T cells) in response to OVA peptide. CpG ODN could significant enhance the survival of CD8+ T cells and IFN-γ production. To further extend these observations to tumor Ag, MUC1 transgenic (Tg) mice that are tolerized to MUC1 Ag, resembling cancer patients, were immunized with anti-CD19 conjugated MUC1 with or without CpG ODN. The data demonstrated that MUC1 conjugates in combination with CpG ODN elicit high-titer anti-MUC1 Abs. In addition, MUC1-specific cytotoxicity and vigorous IFN-γ secretion was generated. In contrast, Tg mice immunized with MUC1 peptide, even in the presence of CpG ODN, did not elicit Ab production and T cell responses. These results indicated that Ag targeted to B cells via CD19 in combination with TLR agonist could reverse immunological tolerance to MUC1 Ag and generate MUC1-specific B cell and T cell responses.