Abstract
Cell penetrating peptides (CPP), including the TAT peptide from the human immunodeficiency virus transactivator of transcription (HIV-TAT) protein and penetratin from Drosophila Antennapedia homeodomain protein, translocate various cargos including peptides and proteins across cellular barriers. This mode of delivery has been harnessed by our group and others to deliver antigenic proteins or peptides into the cytoplasm of antigen processing cells (APC) such as monocyte-derived dendritic cells (MoDC). Antigens or T cell epitopes delivered by CPP into APC in vivo generate antigen-specific cytotoxic T cell and helper T cell responses in mice. Furthermore, mice immunised with these peptides or proteins are protected from a tumour challenge. The functional properties of CPP are dependent on the various cargos being delivered and the target cell type. Despite several studies demonstrating superior immunogenicity of TAT and Antp-based immunogens, none has compared the immunogenicity of antigens delivered by TAT and Antp CPP. In the current study we demonstrate that a cytotoxic T cell epitope from the mucin 1 (MUC1) tumour associated antigen, when delivered by TAT or Antp, generates identical immune responses in mice resulting in specific MUC1 T cell responses as measured by in vivo CTL assays, IFNγ ELISpot assays and prophylactic tumour protection.
Highlights
Fundamental to an effective vaccine is the delivery of antigens to antigen presenting cells (APC) and the ensuing processing and presentation of epitopes to cytotoxic T cells or helper T cells in the context of a relevant MHC haplotype to activate T cells and induce an immune response [1,2]
We have extensively used Antp in our studies of vaccine constructs for the delivery of intact proteins, such as ovalbumin (OVA) and mucin 1 (MUC1), as well as peptides comprised of single cytotoxic T cell or helper T cell epitopes or multiepitope peptides consisting of CD4 and CD8 epitopes [11,12,14,15,16,18]
TATMUC1Kb at varying concentrations were added to DC2.4 cells and cell death was measured quantitatively by lactate dehydrogenase (LDH) levels, a stable cytosolic enzyme that is released upon cell lysis
Summary
Fundamental to an effective vaccine is the delivery of antigens to antigen presenting cells (APC) and the ensuing processing and presentation of epitopes to cytotoxic T cells or helper T cells in the context of a relevant MHC haplotype to activate T cells and induce an immune response [1,2]. We have extensively used Antp in our studies of vaccine constructs for the delivery of intact proteins, such as ovalbumin (OVA) and mucin 1 (MUC1), as well as peptides comprised of single cytotoxic T cell or helper T cell epitopes or multiepitope peptides consisting of CD4 and CD8 epitopes [11,12,14,15,16,18] Mice immunised with these peptides or proteins were protected from a lethal tumour challenge. SIINFEKL from the model antigen ovalbumin (OVA) (TATSIIN, AntpSIIN), or to the H-2Kb CD8 9-mer epitope SAPDTRPAP from the human tumour associated antigen mucin 1 (MUC1) (TATMUC1Kb, AntpMUC1Kb) These studies showed that the tandem fusion peptide of Antp with SIINFEKL was immunogenic in mice, whereas TAT fused to SIINFEKL was not. The immunogenicity of the MUC1 cytotoxic T cell epitope fused in tandem to either TAT or Antp CPP was identical
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