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
  • 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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