Neuronal MHC I is competent to present peptide antigens and to be targeted by antigen specific CD8+T cells 9244

Abstract Description CD8+ T cell responses to neuronal antigens are believed to contribute to CNS autoimmune diseases and neurodegenerative disease pathophysiology. However, the specific endogenous human neuron antigens and their MHC restrictions remain unknown. We characterized the immunopeptidome of human iPSC-derived neurons and verified their ability to elicit cytopathic responses in autologous T cells. After maturation, >100M neurons were treated with IFNg to induce MHC I expression. MHC class I molecules were immunoprecipitated, and associated peptides were analyzed using mass spectrometry. For comparison we also analyzed identically treated human adult dermal fibroblasts and neural ectoderm cells, and neurons differentiated from B2M KO NSCs. Immunopeptidomes were analyzed my Gibbs clustering, netMHC affinity and immunogenicity prediction for patient allotypes. We identified peptides uniquely presented by IFNg-treated neurons and analyzed these for brain enrichment. Among neural enriched proteins detected across multiple subjects, proteins for which CNS autoimmunity has been described were found to be enriched. We also identified putative immunodominant peptides from 29 potential MS patient autoantibody targets (including CRYAB) presented by MHC I on human neurons. Finally, human neurons transduced to express immunodominant peptides from CMV, EBV, and influenza (CEF) showed detectable MHC I peptide presentation and could be injured by autologous CEF-stimulated CD8+ T cells by live imaging. Funding Sources Don and Fran Herdrich NIH grant NS064571 (to CLH) Mayo Clinic Eugene and Marcia Applebaum fellowship award (to BDSC) The Center for Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic (to CLH). Topic Categories Neuroimmunology (NEUR)