Signal peptides


Traditional vaccines are based on dead or attenuated pathogens (Artenstein, 2008), which can be potentially dangerous or difficult to maintain in ambient conditions. An alternative to wholepathogen based vaccines are subunit peptide vaccines (Brossart et al., 2000). These vaccines are composed of small peptides presented to T lymphocytes in the context of MHC molecule (Agudelo and Patarroyo, 2010). These peptides are fully synthetic, nonhazardous and usually easy to maintain in ambient conditions, enabling the vaccination of populations in countries with lower medical standards. An important issue in the design of such vaccines is the choice of optimal epitopes that can induce the maximal immune activation in the largest fraction of the population. Numerous methodologies have been introduced to design optimal multi-epitope vaccines that could cater to a large proportion of the population. These methodologies were usually based on combining peptides that bind highly frequent MHC alleles from a single antigen (Ossendorp et al., 1998; Porgador et al., 1996) or from several antigens (Odunsi et al., 2007; Surman et al., 2000; Toussaint et al., 2008; van Mierlo et al., 2004; Vider-Shalit et al., 2007b; Welters et al., 2008). In this study we test the possibility of a novel alternative of selecting highly immunogenic regions containing multiple epitopes, based on their protein domain identity. MHCclass Imolecules, found on all nucleated cells and platelets, are loaded with peptides which are representative of the protein repertoire of these cells. The antigen presentation machinery in eukaryotic cells breaks down all intracellular proteins into short peptides by the proteasome. The proteasome has three subunits: LMP2, LMP7 and LMP10, with different protease or peptidase activities. Some of the generated peptides have lengths enabling their binding to MHC class I. The transport of proteasome-degraded peptides into the endoplasmic reticulum (ER) involves an ATPdependent transporter designated TAP (Lindquist et al., 1998; Lyko et al., 1995; Martoglio and Dobberstein, 1998). The TAP is a membrane-spanning heterodimer consisting of TAP1 and TAP2 subunits. TAP from different organisms have different preferences for transported peptides based on the hydrophobicity or the charge of the C terminus and of other parts of the transported peptide. In order for a peptide to serve as a good CD8+ Cytotoxic T Lymphocyte (CTL) epitope, it must be cleaved, transferred to the ER and then bind with sufficient affinity to MHC-I molecules. Click here to download the full article