Clonally expanded CD8 T cells recognize cryptic epitopes induced by TDP-43 pathology 3160

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)