TDP-43 pathology induces CD8⁺ T cell activation through cryptic epitope recognition

Area of Science:

• Neuroimmunology
• Molecular Biology
• Proteinopathies

Background:

• TDP-43 aggregation and nuclear loss characterize ALS and IBM.
• This dysfunction causes aberrant cryptic splicing, producing novel proteins.
• CD8+ T cell responses are implicated in TDP-43 proteinopathies, but antigens are unknown.

Purpose of the Study:

• To investigate if cryptic peptides from aberrant splicing act as neo-antigens in ALS and IBM.
• To identify specific T cell antigens associated with TDP-43 pathology.

Main Methods:

• Detection of TDP-43 cryptic exons (e.g., HDGFL2) in IBM muscle.
• Analysis of T cell enrichment and antigen presentation pathways.
• Identification of T cell epitopes from cryptic peptides (HDGFL2, IGLON5).
• Characterization of T cell receptor (TCR) recognition and T cell killing of TDP-43 deficient astrocytes.

Main Results:

• HDGFL2 cryptic peptide and other TDP-43 cryptic exons found in IBM muscle.
• Presence of cryptic exons correlates with T cell infiltration and MHC class I presentation.
• Specific epitopes from HDGFL2 and IGLON5 recognized by CD8+ T cells in ALS/IBM patients.
• Engineered T cells with identified TCRs recognize cryptic epitopes and kill TDP-43 deficient astrocytes.

Conclusions:

• This study identifies specific T cell antigens in ALS and IBM for the first time.
• The findings directly link adaptive immune responses to TDP-43 pathology.
• Cryptic peptides resulting from TDP-43 dysfunction serve as neo-antigens, driving T cell activation in these diseases.