Empirically, however, these strategies have not been successful. In the current study, we profiled the early activation of CD8+ T cells by MHC class I-restricted peptide immunization to better understand the biology of this response. We found that

CD8+ T cells proliferated robustly in response to low doses of short synthetic peptides in PBS, but failed to acquire effector function or form memory populations in the absence of the TLR ligand CpG. CpG was unique among TLR ligands in its ability to enhance the response to peptide and its adjuvant effects had strict temporal requirements. Interestingly, CpG treatment modulated T-cell expression of the surface receptors PD-1 and CD25, providing insight into its possible adjuvant mechanism. The effects of CpG on MI-503 peptide immunization were dramatically

enhanced in the absence of B cells, demonstrating a unique system of regulation of T-cell responses by these lymphocytes. The results reported here provide insight into the complex response to a simple vaccination regimen, as well as a framework for a rational peptide-based check details vaccine design to both exploit and overcome targeted aspects of the immune response. CD8+ T cells specific for the SYVPSAEQI epitope of the Plasmodium yoelii circumsporozoite (CS) protein are induced by immunization with radiation-attenuated sporozoites and strongly inhibit the development of liver stage parasites 1–5. In view of their efficiency at inducing protective immunity, attenuated

parasites have been proposed as a vaccine for humans. Obtaining these parasites is, however, a laborious and costly process, as they need to be isolated aseptically from the salivary glands of infected mosquitoes and maintained in a viable state until immediately before vaccination. As an alternative approach, the development of subunit vaccines containing parasite-derived those antigenic moieties has been the focus of research in many laboratories in the last two decades. While encouraging results have been obtained on the induction of protective humoral responses, only modest success has been achieved on the induction of protective parasite-specific T-cell-mediated immune responses. Immunization with short synthetic peptides encompassing MHC class I-restricted epitopes could be – in principle – the simplest subunit vaccine that targets the adaptive immune system. Peptide-based vaccination strategies would have many advantages, including low cost, safety, stability and ease of synthesis and modification. However, peptide vaccine approaches have not been successful.