Peptide Presentation Is the Key to Immunotherapeutical Success

Abstract

Positive and negative selection in the thymus relies on T-cell receptor recognition of peptides presented by HLA molecules and determines the repertoire of T cells. Immune competent T-lymphocytes target cells display nonself or pathogenic peptides in complex with their cognate HLA molecule. A peptide passes several selection processes before being presented in the peptide binding groove of an HLA molecule; here the sequence of the HLA molecule's heavy chain determines the mode of peptide recruitment. During inflammatory processes, the presentable peptide repertoire is obviously altered compared to the healthy state, while the peptide loading pathway undergoes modifications as well. The presented peptides dictate the fate of the HLA expressing cell through their (1) sequence, (2) topology, (3) origin (self/nonself). Therefore, the knowledge about peptide competition and presentation in the context of alloreactivity, infection or pathogenic invasion is of enormous significance. Since in adoptive cellular therapies transferred cells should exclusively target peptide-HLA complexes they are primed for, one of the most crucial questions remains at what stage of viral infection viral peptides are presented preferentially over self-peptides. The systematic analyzation of peptide profiles under healthy or pathogenic conditions is the key to immunological success in terms of personalized therapeutics.

The Impact of the ‘Mis-Peptidome’ on HLA Class I-Mediated Diseases: Contribution of ERAP1 and ERAP2 and Effects on the Immune Response

“…In particular, the non-covalent interaction of the drug with the F pocket of HLA-B*57:01 dramatically alters the self-epitope repertoire displayed by the HLA molecule creating foreign complexes, which induce robust T cell responses in the HLA-B*57:01 carriers taking abacavir [ 6 , 7 , 8 ]. Moreover, several viruses (i.e., HIV, CMV, EBV) could contribute to the alteration of the peptide repertoire establishing their strategies to escape immune surveillance [ 9 ].…”

HLA-F Allele-Specific Peptide Restriction Represents an Exceptional Proteomic Footprint

“…Peptide presentation is the main key to immune recognition [5]; the features of bound peptides determine the structure of an HLA molecule, and therefore, the recognition of its cognate receptor [6,7]. The amino acid composition of the HLA heavy chain dictates the mode of peptide selection [8,9], and therefore, the origin, the sequence and the binding affinity of a finally presented peptide.…”