Unconventional epitope discovery through reverse immunology

Michele Mishto (primary)
King's College London
Adrian Shepherd (secondary)
Institute of Structural and Molecular Biology
Birkbeck, University of London


The collection of epitopes this is presented on cell surfaces drives the CD8+ T cell response and determines how the healthy status of each individual is patrolled. Recently, many tools and strategies have been developed for predicting which set of peptide fragments constitute conventional epitopes that can be recognised by CD8+ T cells. The aim of this project is to develop computational strategies for predicting and identify unconventional antigenic peptides, and to validate them in various in vitro and in cellulo systems. This project is highly interdisciplinary, involving substantial elements of computational modelling, immuno-biochemistry and wet-lab work.


Ebstein, F., Textoris-Taube, K., Keller, C., Golnik, R., Vigneron, N., Van den Eynde, B. J., Schuler-Thurner, B., Schadendorf, D., Lorenz, F. K., Uckert, W., et al. (2016). Proteasomes generate spliced epitopes by two different mechanisms and as efficiently as non-spliced epitopes. Sci Rep 6, 24032.
Kuckelkorn, U., Stubler, S., Textoris-Taube, K., Kilian, C., Niewienda, A., Henklein, P., Janek, K., Stumpf, M. P. H., Mishto, M., and Liepe, J. (2019). Proteolytic dynamics of human 20S thymoproteasome. J Biol Chem 294, 7740-7754.
Liepe, J., Holzhutter, H. G., Bellavista, E., Kloetzel, P. M., Stumpf, M. P., and Mishto, M. (2015). Quantitative time-resolved analysis reveals intricate, differential regulation of standard- and immuno-proteasomes. Elife 4, e07545.
Liepe, J., Marino, F., Sidney, J., Jeko, A., Bunting, D. E., Sette, A., Kloetzel, P. M., Stumpf, M. P., Heck, A. J., and Mishto, M. (2016). A large fraction of HLA class I ligands are proteasome-generated spliced peptides. Science 354, 354-358.
Liepe, J., Sidney, J., Lorenz, F. K. M., Sette, A., and Mishto, M. (2019). Mapping the MHC Class I-Spliced Immunopeptidome of Cancer Cells. Cancer Immunol Res 7, 62-76.
Mansurkhodzhaev, A., Barbosa, C. R. R., Mishto, M., and Liepe, J. (2021). Proteasome-Generated cis-Spliced Peptides and Their Potential Role in CD8(+) T Cell Tolerance. Front Immunol 12, 614276.
Mishto, M., and Liepe, J. (2017). Post-Translational Peptide Splicing and T Cell Responses. Trends Immunol 38, 904-915.
Mishto, M., Mansurkhodzhaev, A., Rodriguez-Calvo, T., and liepe, J. (2021). Potential mimicry of viral and pancreatic beta cell antigens through non-spliced and cis-spliced zwitter epitope candidates in Type 1 Diabetes. Front Immunol 12, 656451.
Mishto, M., Mansurkhodzhaev, A., Ying, G., Bitra, A., Cordfunke, R. A., Henze, S., Paul, D., Sidney, J., Urlaub, H., Neefjes, J., et al. (2019). An in silico-in vitro Pipeline Identifying an HLA-A(*)02:01(+) KRAS G12V(+) Spliced Epitope Candidate for a Broad Tumor-Immune Response in Cancer Patients. Front Immunol 10, 2572.

Molecules, cells and industrial biotechnology
Area of Biology
Techniques & Approaches
BiochemistryBioinformaticsMathematics / StatisticsMolecular Biology