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

作者：Shahab Chizari, Matteo Zanovello, Steven Lingyang Kong, Vidur J. Saigal, Anna‐Leigh Brown, Valentina Turchetti, Bingxian Chen, Connor C. Devine, Luca Zampedri, Iwona Skorupinska, Giacomo Maria Minicuci, Francesca Paron, Paola Tonin, Giulia Marchetto, Ziyi Li, Jennifer M. Colón-Mercado, Simone Barattucci, Darija Soltic, Dario Dattilo, Ariana Gatt, Jada M. Hembrador, Guido Capasso, Federica Frezzato, Livio Trentin, Elisabeth Lin, Raquel Lopes, Nathan Routledge, Yue A. Qi, Michael G. Hanna, Michael Ward, Leonard Petrucelli, Maurizio Romano, Gaetano Vattemi, Emanuele Buratti, Andrea Malaspina, Ashirwad Merve, Pedro Machado, Gianni Sorarú, Pietro Fratta, Ning Jiang · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.06.22.660773 · 被引用次数：8 · 研究领域：CAR-T cell therapy research、Immunotherapy and Immune Responses、T-cell and B-cell Immunology

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...