Year: 2025
Type: article
Abstract: Description Aggregation of the RNA binding protein TDP-43 is a shared pathological feature in several neurodegenerative and inflammatory conditions. The resulting loss of function of TDP-43 leads to splicing defects and aberrant inclusion of cryptic exons (CEs), intronic sequences that are normally excluded from mRNA. While clonally expanded and highly differentiated CD8+ T cells have been observed to be particularly enriched in individuals with TDP-43 proteinopathies, their target antigens have remained elusive. In our work, we show that individuals with amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM) harbor clonally expanded populations of CD8+ T cells whose cognate epitopes are derived from CEs, particularly within HDGFL2 and IgLON5 proteins. We demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to CEs and are able to kill TDP-43 deficient cells. Finally, we identify a high expression of HDGFL2 cryptic peptide in IBM skeletal muscle, co-localized with TDP-43 pathology, alongside an enrichment of T cell and class I antigen presentation pathways. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking inflammation to TDP-43 pathology. Topic Categories Neuroimmunology (NEUR)
Source: The Journal of Immunology
Authors: Shahab Chizari, Matteo Zanovello, Lingyang Kong, Vidur J. Saigal, Pietro Fratta, Ning Jiang
Institutions: University of Pennsylvania, University College London
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416451323
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