pMHC Structural Comparisons as a Pivotal Element to Detect and Validate T-Cell Targets for Vaccine Development and Immunotherapy-A New Methodological Proposal

• Published in: Cells (Basel, Switzerland) Switzerland), 2019-11, Vol.8 (12), p.1488
• Main Authors: Vianna, Priscila, Mendes, Marcus F A, Bragatte, Marcelo A, Ferreira, Priscila S, Salzano, Francisco M, Bonamino, Martin H, Vieira, Gustavo F
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Antigen presentation; Antigens; Bioinformatics; Cancer; cancer targets discovery; cellular immunology; Cytotoxicity; Epitopes; Epitopes - immunology; Histocompatibility antigen HLA; Humans; Hypothesis; Immune response (cell-mediated); Immune system; Immunogenicity; Immunotherapy; immunotherapy targets; Infections; Investigations; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Major Histocompatibility Complex - immunology; Mutation; Pathogens; Peptides; Peptides - chemistry; Peptides - immunology; Pipelines; Proteins; Receptors, Antigen, T-Cell - immunology; Reproducibility of Results; T cell receptors; T-Lymphocytes - immunology; Topography; Vaccine development; Vaccines; viral epitopes; Viral infections; Viral Vaccines - immunology; Viruses
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells8121488

The search for epitopes that will effectively trigger an immune response remains the "El Dorado" for immunologists. The development of promising immunotherapeutic approaches requires the appropriate targets to elicit a proper immune response. Considering the high degree of HLA/TCR diversity, as well as the heterogeneity of viral and tumor proteins, this number will invariably be higher than ideal to test. It is known that the recognition of a peptide-MHC (pMHC) by the T-cell receptor is performed entirely in a structural fashion, where the atomic interactions of both structures, pMHC and TCR, dictate the fate of the process. However, epitopes with a similar composition of amino acids can produce dissimilar surfaces. Conversely, sequences with no conspicuous similarities can exhibit similar TCR interaction surfaces. In the last decade, our group developed a database and in silico structural methods to extract molecular fingerprints that trigger T-cell immune responses, mainly referring to physicochemical similarities, which could explain the immunogenic differences presented by different pMHC-I complexes. Here, we propose an immunoinformatic approach that considers a structural level of information, combined with an experimental technology that simulates the presentation of epitopes for a T cell, to improve vaccine production and immunotherapy efficacy.