Tuberculosis is a leading cause of mortality worldwide with nearly 1.5 million deaths every year. Recognition of the causative agent, Mycobacterium tuberculosis, by the immune system and T cell activation requires efficient presentation of peptides by antigen presenting cells, such as dendritic cells and macrophages. However, the available Bacillus Calmette-Guerin (BCG) vaccine offers incomplete and variable protection, necessitating research into novel vaccines.
Novel Mycobacterium tuberculosis antigens for vaccine design
The MTBHLAE project investigated the process of antigen presentation in tuberculosis and especially the role of HLA-E restricted T cells. The research, undertaken with the support of the Marie Skłodowska Curie (MSC) programme, aimed to identify novel Mycobacterium tuberculosis-derived peptides that could be presented by the HLA-E antigen-presenting molecules for activation of protective T cells. “HLA-E is an interesting molecule for vaccine design because it displays very little variation in humans, contrary to other HLA molecules,” explains the MSC research fellow Paula Ruibal. The team focused on understanding the prerequisites for peptides to bind HLA-E molecules and used this information to improve a prediction algorithm for discovering novel Mycobacterium tuberculosis-derived peptides. Researchers applied an innovative peptide-binding assay which allowed them to relatively quantify HLA-E binding to hundreds of different peptide sequences. They also made substitutions on various positions of known high and moderate peptide binders to HLA-E to investigate how this substitution could impede or promote peptide binding. Subsequent analysis of the peptide-binding motif helped them to understand the molecular requirements for any peptide to bind HLA-E. Results showed that apart from the peptide main anchor positions on HLA-E, binding can also be influenced by other sites which might affect the neighbouring positions. Interestingly, the human, mouse and non-human primate homologues demonstrated considerable differences in peptide binding despite their highly conserved sequence. Further investigation is necessary to reveal if this is due to stability variations or true differences in peptide-binding motifs.
MTBHLAE significance and future plans
“The project has contributed important insight into the HLA-E peptide binding requirements which lay the foundation to identify alternative pathogen-derived peptides,” emphasises Ruibal. The prediction algorithm constitutes an indispensable tool towards the identification of peptides that can trigger HLA-E-restricted effector T cell immunity against Mycobacterium tuberculosis. Moreover, it can predict peptides derived from any protein sequence of interest, expanding its application in other infectious diseases and malignancies. The fact that HLA-E is a molecule conserved in all humans, it renders it an interesting target for vaccine design as it can be applied regardless of genetic background. The MTBHLAE approach can be implemented not only for the design of optimised vaccine strategies, but also for advancing our understanding of HLA-E-restricted T cell immunobiology. The scientific team is currently testing the capacity of newly predicted Mycobacterium tuberculosis-derived peptides to induce HLA E restricted T cell responses. They have received extra funding to characterise the T-cell responses induced by these peptides in the context of controlling Mycobacterium tuberculosis infection in vivo in mice and in human cohorts. This study will be carried out in collaboration with the University of Cape Town in South Africa, among other partners.
MTBHLAE, HLA-E, tuberculosis, vaccine, Mycobacterium tuberculosis, algorithm, T cells