The human leukocyte antigen (HLA) proteins are an indispensable component of adaptive immunity because of their role in presenting self and foreign peptides to T cells. Further, many complex diseases are associated with genetic variation in the HLA region, implying an important role for specific HLA-presented peptides in the etiology of these diseases. Identifying the specific set of peptides presented by an individual's HLA proteins in vivo, as a whole being referred to as the immunopeptidome, has therefore gathered increasing attention for different reasons. For example, identifying neoepitopes for cancer immunotherapy, vaccine development against infectious pathogens, or elucidating the role of HLA in autoimmunity. Despite the tremendous progress made during the last decade in these areas, several questions remain unanswered. In this perspective, we highlight five remaining key challenges in the analysis of peptide presentation and T cell immunogenicity and discuss potential solutions to these problems. We believe that addressing these questions would not only improve our understanding of disease etiology but will also have a direct translational impact in terms of engineering better vaccines and in developing more potent immunotherapies.

Keywords: HLA-II & autoimmunity; TCR - T cell receptor; immunogenicitiy; immunotherapy; mass-spectrometry (MS) based immunopeptidomics; neoantigen.

Copyright © 2023 ElAbd, Bacher, Tholey, Lenz and Franke.

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