Rational Design of Vaccination Strategies to Promote Antigen Entry into the MHC Class I-Restricted Presentation Pathway

Abstract

Cytotoxic CD8+ T lymphocytes (CTLs) constitute one of the main effector mechanisms against tumors and viral infections. CTLs specifically recognize short peptides (8-10 residues long) displayed on the surface of ‘target’ cells, which result from the processing of foreign or abnormal proteins (e.g. virus and tumor proteins) and are bound to major histocompatibility complex (MHC) class I molecules. Virtually all nucleated cells display on their surface fragments of intracellularly produced polypeptides. When there are signs of invasion or transformation, CTLs take control of the situation by destroying these ‘labeled’ target cells. This is an extremely efficient mechanism. However, the efficient differentiation of naïve CD8+ T cells into CTLs is a limiting prerequisite. To achieve this differentiation, dendritic cells (DCs) are critical since only these professional antigen-presenting cells (APCs) can provide not only the peptide presented onto the MHC class I molecules but also the costimulatory signals required for this activation. To this end, DCs take up antigens and degrade them into peptides which are loaded on MHC class I and presented onto the surface to prime specific T lymphocytes. In this review, we summarize the current knowledge on the mechanisms used by professional APCs in the processing and presentation of endogenous and exogenous antigens in the context of MHC class I molecules (i.e. priming and cross-priming). We will also discuss new vaccination strategies that take advantage of these physiological mechanisms in order to improve the elicitation of cytotoxic responses to eliminate intracellular pathogens and tumors.

Emerging Concepts and Technologies in Vaccine Development

“…However, DC-directed RNA vaccines are currently limited by the restrained immune environment present in cancers, which can limit the activity of DCs and increases the activity of regulatory T cells (216,220,221). It is thought that these challenges could be mitigated by optimizing the use of cytokines and other factors that would act as adjuvants in combination with cancer RNA vaccines (195,(222)(223)(224)(225) and by optimizing DC isolation and culturing conditions (226). A few DC-directed RNA vaccine candidates are currently in clinical trials, including those in phase III (196,221).…”