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

Abstract

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.

MUC22, HLA-A, and HLA-DOB variants and COVID-19 in resilient super-agers from Brazil

“…Hierarchical clustering analysis showed that four out of eight investigated alleles presented an electrostatic potential distribution fingerprint in the probed area. This physicochemical element was already described as pivotal to cytotoxicity elicitation, as described previously ( 80 ).…”

Viral immunogenic footprints conferring T cell cross-protection to SARS-CoV-2 and its variants

“…All the recovered epitopes for Alpha and Beta Coronaviruses and analysed VOCs were modeled in HLA-A*02:01 context to investigate their TCR interaction surfaces looking for immunogenicity fingerprints and shared structural features. The full applied rationale can be found in ( 53 ). The Docktope tool ( ) allowed to produce pMHC models containing the analysed peptides anchored to the HLA-A*02:01 Class I MHC (pMHC).…”