Decoding antigen specific T cells in frontotemporal degeneration

About This Grant

Abstract Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder characterized by progressive frontal and/or temporal lobe atrophy. In approximately 50% of cases, FTD is associated with TAR DNA-binding protein 43 (TDP-43) pathology, including nuclear depletion and cytoplasmic aggregation, which can lead to the generation of cryptic exons (CEs). Emerging evidence suggests that these cryptic peptides may be recognized by the immune system, contributing to disease pathology. CD8+ T cell infiltration has been observed in FTD patient brains, and C9orf72-related ALS/FTD mouse models show CD8+ T cell accumulation alongside microglial activation. However, the antigen targets, functional phenotypes, and temporal dynamics of these T cells remain poorly characterized. Our preliminary data, using cryptic peptides validated by mass spectrometry, show that CD8+ T cells from ALS and IBM patients recognize these cryptic peptides, undergo clonal expansion, and exhibit activation markers. Furthermore, CD8+ T cells transduced with cryptic-specific TCRs induce cytotoxicity toward astrocytes with TDP-43 knockdown, demonstrating the potential for cryptic peptides to be naturally processed and presented in neuronal cells. Given the shared pathology of cryptic exon production across ALS, IBM, and FTD, we hypothesize that clonally expanded CD8+ T cells in C9-FTD patients recognize cryptic peptides, with greater expansion in symptomatic compared to pre-symptomatic patients. In collaboration with Dr. Corey McMillan at the Penn FTD Center, we will test this hypothesis and establish a link between CD8+ T cells and FTD progress. This study will provide crucial first insights into the possible role of antigen-specific CD8+ T cells play in FTD pathology, paving the way for potential immunotherapeutic strategies targeting cryptic epitope-specific T cells.