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

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Researchers identified novel T cell antigens in amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM). These cryptic epitopes arise from TDP-43 protein dysfunction, linking the adaptive immune response to these neurodegenerative diseases.

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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.