2. Academic Validation
  3. TDP-43 pathology induces CD8+ T cell activation through cryptic epitope recognition

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

  • bioRxiv. 2025 Jul 14:2025.06.22.660773. doi: 10.1101/2025.06.22.660773.
Shahab Chizari 1,  Matteo Zanovello 2,  Steven Kong 1,  Vidur Saigal 1,  Anna-Leigh Brown 2,  Valentina Turchetti 2,  Luca Zampedri 2,  Iwona Skorupinska 2,  Giacomo Maria Minicuci 3,  Francesca Paron 4,  Paola Tonin 5,  Giulia Marchetto 5,  Ziyi Li 6,  Jennifer M Colón-Mercado 7,  Dario Dattilo 2,  Simone Barattucci 2,  Ariana Gatt 2,  Andy Qi 6,  Michael Hanna 2,  Michael Ward 6 7,  Leonard Petrucelli 8,  Maurizio Romano 9,  Gaetano Vattemi 5,  Emanuele Buratti 4,  Andrea Malapsina 2,  Ashirwad Merve 2,  Pedro M Machado 2 10,  Gianni Soraru 3,  Pietro Fratta 2 11,  Ning Jiang 1 12 13 14 15 16
Affiliations

Affiliations

  • 1 Department of Bioengineering, University of Pennsylvania, Philadelphia, USA.
  • 2 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, UK.
  • 3 Padua Neuroscience Centre, University of Padua, Italy.
  • 4 International Centre for Genetic Engineering and Biotechnology.
  • 5 Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy.
  • 6 Center for Alzheimer's and Related Dementias, NIH.
  • 7 National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
  • 8 Mayo Clinic College of Medicine and Science, Mayo Clinic, USA.
  • 9 Department of Life Sciences, University of Trieste, Italy.
  • 10 NIHR University College London Hospitals Biomedical Research Centre.
  • 11 The Francis Crick Institute, London, UK.
  • 12 Penn Institute for Immunology and Immune Health, University of Pennsylvania, Philadelphia.
  • 13 Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia.
  • 14 Abramson Cancer Center, University of Pennsylvania, Philadelphia.
  • 15 Institute for RNA Innovation, University of Pennsylvania, Philadelphia.
  • 16 Penn Center for Precision Engineering for Health, University of Pennsylvania, Philadelphia, USA.
PMID: 40667053 DOI: 10.1101/2025.06.22.660773
Abstract

Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features of amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), two degenerative diseases of the CNS and muscle. The loss of TDP-43 nuclear function results in the aberrant inclusion of cryptic exons in mRNA transcripts, leading to the expression of de novo proteins. Clonally expanded and highly differentiated CD8+ T cells have been observed in individuals with TDP-43 proteinopathies and therapeutics modulating the T cell response have recently been found to extend survival. However, the target antigens mediating T cell activation have remained elusive. Here, we investigate whether the de novo proteins induced by aberrant cryptic splicing due to TDP-43 nuclear loss can act as neo-antigens. We detect the HDGFL2 cryptic peptide and multiple Other TDP-43 cryptic exons in IBM skeletal muscle, where their presence correlates with enrichment of T cells and class I antigen presentation pathways. Furthermore, we identify epitopes deriving from HDGFL2 and IGLON5 cryptic peptides which are recognized by clonally expanded and functionally differentiated populations of CD8+ T cells in ALS and IBM Patients. Finally, we demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to the cryptic peptide derived epitopes (cryptic epitopes) and are able to kill TDP-43 deficient astrocytes. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology.

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