TCR contact residue hydrophobicity is a hallmark of immunogenic CD8⁺T cell epitopes

Abstract

Despite the availability of major histocompatibility complex (MHC)-binding peptide prediction algorithms, the development of T-cell vaccines against pathogen and tumor antigens remains challenged by inefficient identification of immunogenic epitopes. CD8+ T cells must distinguish immunogenic epitopes from nonimmunogenic self peptides to respond effectively against an antigen without endangering the viability of the host. Because this discrimination is fundamental to our understanding of immune recognition and critical for rational vaccine design, we interrogated the biochemical properties of 9,888 MHC class I peptides. We identified a strong bias toward hydrophobic amino acids at T-cell receptor contact residues within immunogenic epitopes of MHC allomorphs, which permitted us to develop and train a hydrophobicity-based artificial neural network (ANN-Hydro) to predict immunogenic epitopes. The immunogenicity model was validated in a blinded in vivo overlapping epitope discovery study of 364 peptides from three HIV-1 Gag protein variants. Applying the ANN-Hydro model on existing peptide-MHC algorithms consistently reduced the number of candidate peptides across multiple antigens and may provide a correlate with immunodominance. Hydrophobicity of TCR contact residues is a hallmark of immunogenic epitopes and marks a step toward eliminating the need for empirical epitope testing for vaccine development.

Tumor neoantigens: building a framework for personalized cancer immunotherapy

“…For the one patient in the cohort whose tumor neoantigen was defined, neoantigen-specific T cell responses paralleled tumor regression, implicating a link between the T cell responses and the antitumor effects of anti-PD-1 therapy. A recent report by Chowell et al used bioinformatics approaches to support an argument that the hydrophobicity of TCR contact residues form a hallmark of immunogenic epitopes (95). Thus it is clear that more work is needed to clarify whether there are amino acid motifs that play important roles in determining neoantigenicity.…”

Myelin-derived and putative molecular mimic peptides share structural properties in aqueous and membrane-like environments

“…It is obvious that many hydrophobic self-sequences are strongly immunogenic [92,93], but the corresponding T cells go to apoptosis in the thymus. An animal model with genetic or external exposure of myelin proteins/peptides, which do not significantly change the structure of the host protein, but alter membrane-induced conformational changes, might be useful to test these hypotheses.…”

“…Nine peptides from four human or mouse compact myelin proteins with a putative autoimmunogenic character and four viral/bacterial peptides suggested [19] to mimic the well-known MS-associated MBP sequence (amino acids [85][86][87][88][89][90][91][92][93][94][95][96][97][98][99] were chosen for structural analysis; all peptides have been described in the literature earlier (see Table 1 and references therein). The corresponding MBP85-99 peptide was a subject of our earlier study [31].…”

A generalized framework for computational design and mutational scanning of T-cell receptor binding interfaces

“…Increasing buried hydrophobic surface area is a well-known strategy for enhancing binding, and the rigid, bulky and amphipathic nature of tyrosine and tryptophan provide structural and chemical utility (Koide and Sidhu, 2009). Highly antigenic peptides have a tendency to be enriched in hydrophobic amino acids in TCR contact sites (Chowell et al, 2015), potentially indicating that such amino acids are indeed optimal for enhancing TCR affinity.…”