Characterization of disease restricted antigen-specific CD8 T cells in TDP-43 pathology 4476

Abstract Description The aggregation and nuclear depletion of TAR DNA-binding protein-43 (TDP-43) are pathologically linked to the progression of various neurodegenerative diseases. The loss of function of TDP-43 leads to the generation of cryptic exons, some of which can be translated into cryptic peptides in the brain. We have identified clonal CD8 T cell populations specific to various cryptic peptides. To deeply characterize these antigen-specific CD8 T cell populations, we engineered human T cells expressing these T cell receptors (TCRs). Some TCRs showed restricted binding and activation confined to the core epitope, whereas other TCRs tolerated variations in the epitope sequence. Using a TDP-43-deficient astrocyte cell line, we confirmed TCR-specific cytotoxic activity by co-culturing with activated primary human T cells. To validate whether cryptic peptide specific T cells can be cytotoxic to neurons, we developed a T cell and neuron-based 3D co-culture system with motor neurons derived from TDP-43-deficient iPSC cell line. Overall, our results confirm that TDP-43 cryptic peptides can be processed, presented on MHC class I molecules on the surface of neural cells, and recognized by cryptic-epitope-specific TCRs. These findings highlight the susceptibility of neural cells to CD8+ T cell-mediated cytotoxicity and implicate CD8+ T cells in the pathogenesis of TDP-43 proteinopathies. Funding Sources IFI pilot award 2022, CZI Brain Topic Categories Neuroimmunology (NEUR)