T cell responses to viral infections - opportunities for Peptide vaccination

Abstract

An effective immune response against viral infections depends on the activation of cytotoxic T cells that can clear infection by killing virus-infected cells. Proper activation of these T cells depends on professional antigen-presenting cells, such as dendritic cells (DCs). In this review, we will discuss the potential of peptide-based vaccines for prevention and treatment of viral diseases. We will describe features of an effective response against both acute and chronic infections, such as an appropriate magnitude, breadth, and quality and discuss requirements for inducing such an effective antiviral immune response. We will address modifications that affect presentation of vaccine components by DCs, including choice of antigen, adjuvants, and formulation. Furthermore, we will describe differences in design between preventive and therapeutic peptide-based vaccines. The ultimate goal in the design of preventive vaccines is to develop a universal vaccine that cross-protects against multiple strains of the virus. For therapeutic vaccines, cross-protection is of less importance, but enhancing existing T cell responses is essential. Although peptide vaccination is successful in inducing responses in human papillomavirus (HPV) infected patients, there are still several challenges such as choosing the right target epitopes, choosing safe adjuvants that improve immunogenicity of these epitopes, and steering the immune response in the desired direction. We will conclude with an overview of the current status of peptide vaccination, hurdles to overcome, and prospects for the future.

Keywords: DC; acute; chronic; infection; peptides; vaccination; virus.

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Figure 1

Routes of presentation of viral peptides on DCs. Viruses can enter cells by two ways: some viruses can infect cells directly, leading to replication of virus inside the cells. During this process, some of the viral proteins will be degraded into peptide fragments, which will be presented on MHC class I molecules to CD8+ T cells (I). APCs, such as DCs can also take up viral particles or remnants of virally infected cells (II). During processing by professional APCs, viral peptides can be presented on MHC class I molecules via the cross-presentation pathway (III). In parallel, these extracellular-derived peptides will be presented on MHC class II molecules. The TCR of virus-specific CD4+ T can recognize MHC class II-peptide complexes on professional APCs. Next to the interaction of the MHC class II-peptide complex with the TCR, CD4+ T cells can activate DCs by interaction of CD40 with CD40 ligand on the DC (IV). This interaction activates DCs and results in upregulation of maturation markers CD80/CD86. CD80 and CD86 interact with CD28 on naïve CD8+ T cells (V). Together with the recognition of the MHC class I-peptide complex by the TCR, CD28 signaling will result in the activation of the CD8+ T cell (VI). These activated CD8+ T cells will differentiate into effector T cells that can recognize the MHC class I-peptide complex on virally infected cells. Binding of the TCR to the MHC class I-peptide complex leads to activation of the CD8+ T cell and the release of cytotoxic granules containing perforins and granzymes, and the production of cytokines such as TNF-α and IFN-γ (VII).