Clonally expanded cryptic-epitope-specific CD8+ T cells mediate HLA-restricted neurotoxicity in TDP-43-associated frontotemporal dementia 2267088

Abstract Introduction Loss of nuclear repression by TAR DNA-binding protein 43 (TDP-43) in frontotemporal dementia (FTD) induces cryptic exon (CE) inclusion and generation of de novo peptides with potential MHC-I immunogenicity. Although our preliminary work has shown cryptic-epitope-specific CD8+ T cells in amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), their presence, specificity, and functional consequences in FTD remain unknown. Methods We performed DNA-barcoded tetramer screening and single-cell TetTCR-SeqHD profiling on PBMCs from C9orf72- and GRN-associated FTD patients. Identified CE-specific TCRs were reconstructed in human CD8+ T cells to assess HLA-restricted recognition and cytotoxicity toward TDP-43-deficient astrocyte and neuroblastoma models. β₂-microglobulin (β2m) knockdown and cytokine blockade defined antigen and cytokine dependencies. CE-specific TCRs were also redirected into regulatory T cells (Tregs) to evaluate antigen-restricted immune suppression. Results Clonally expanded CE-specific CD8+ T cells were detected in FTD, recognizing epitopes from HDGFL2, IGLON5, and additional FTD-enriched CEs across multiple HLA alleles. These cells displayed effector-memory phenotypes consistent with chronic antigen stimulation. CE-specific TCR-engineered CD8+ T cells selectively recognized and killed HLA-matched, TDP-43-deficient neural cells. This cytotoxicity was abrogated by β2m knockdown, demonstrating an antigen-dependent effector axis. CE-specific TCR-Tregs maintained lineage stability and attenuated CD8+-mediated neural injury in co-culture models. Conclusion These results identify for the first time CE-specific TCRs in FTD, demonstrate their HLA-restricted recognition of neural targets, and establish a mechanistic and regulatory framework linking TDP-43 loss, cryptic epitope presentation, and adaptive immune-mediated neurotoxicity. These findings reveal antigen-specific immunomodulation as a precision therapeutic strategy across the TDP-43 proteinopathy spectrum. Funding Source n/a Topic Categories Neuroimmunology (NEUR)