IMMUNOLOGY2025™ Conference Recordings-Clonally expanded CD8+ T cells recognize cryptic epitopes induced by TDP-43 pathology

Clonally expanded CD8+ T cells recognize cryptic epitopes induced by TDP-43 pathology - Steven Kong

Video Transcription

Video Summary

The speaker presented research showing that TDP-43 pathology can generate cryptic peptides from normally hidden intronic regions, and that some of these peptides are presented by MHC class I and recognized by CD8 T cells. In IBM tissue, cryptic peptide expression co-localized with TDP-43 aggregates and markers of immune activation. In ALS and IBM blood samples, peptide-specific CD8 T cells were enriched, clonally expanded, and often had effector-memory or terminally differentiated phenotypes. Using TCR sequencing, the team identified TCRs specific for cryptic peptides such as HDGFL2 and EGLN5, confirmed their antigen binding, and showed that these TCRs activated T cells in a peptide-specific manner. Finally, TCR-transduced CD8 T cells killed TDP-43-deficient astrocytes in an MHC class I–dependent way. The study links TDP-43 pathology to adaptive immune responses and suggests a route for immune-targeted therapies.

Keywords

TDP-43 pathology

cryptic peptides

MHC class I

CD8 T cells

adaptive immune response