CD8+ T cells recognize de novo epitopes induced by TDP-43 dysfunction.

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Abstract Cytoplasmic aggregation and dysfunction of the DNA-binding protein, TDP-43, is an underlying pathology in disorders including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and inclusion body myositis (IBM). The functional loss of TDP-43 results in aberrant splicing and the inclusion of cryptic exons in hundreds of mRNA transcripts which ultimately lead to the expression of de novo proteins. Whether these de novo proteins can stimulate and activate T cells is unknown but would be critical in understanding the pathogenesis of these disorders. Cryptic peptides are strong candidates for T cell responses as they are likely not presented during T cell selection. Additionally, it has been demonstrated that there are highly differentiated and clonal populations of CD8+ T cells circulating the blood of patients with ALS-4. Therefore, we hypothesize that cryptic peptides induced by TDP-43 aggregation could be recognized by clonally expanded CD8+ T cells that exhibit an activated phenotype. In exploration of our hypothesis, PBMCs from ALS and IBM donors were collected and HLA-genotyped. Cryptic epitopes were bioinformatically predicted using a sliding window approach. From this epitope library, we have generated barcoded and fluorescently tagged peptide-MHC tetramers to capture and single cell sequence cryptic peptide-specific T cells. Preliminary results highlight several populations of circulating CD8+ T cells capable of recognizing cryptic peptides in ALS and IBM.