Microproteins as a potential source of antigens in autoimmunity 3875

Abstract Description Microproteins are tiny proteins, typically smaller than 100 amino acids, often not recognized through conventional genome annotation and mislabeled as being non-functional. It was recently shown that peptide epitopes resulting from microproteins are presented on MHC complexes. However, the immune implications of microprotein expression are not well understood. We hypothesize that expression in the thymus presents a natural filter on microproteins – where those expressed in the thymus are tolerized and are, therefore, more likely to have broad tissue expression and function. On the other hand, microproteins not expressed in the thymus are likely to be restricted to immune-privileged tissues. To interrogate this in the context of Type 1 Diabetes, we first profiled the immunopeptidome and translatome of stem cell-derived pancreatic b-cells and created an epitope library containing ∼60,000 epitopes. We utilize our lab’s antigen discovery platform to investigate whether islet-infiltrating T cell clones derived from T1D patients recognize micropeptide-derived epitopes. We will further compare how the thymic expression of micropeptides targeted by T cells correlates with their immunogenicity. Additionally, we plan to extend this research to other autoimmune conditions to explore the role of microproteins as sources of autoantigens. Topic Categories Basic Autoimmunity (BA)