The landscape of T cell and antigen interactions are critical to disease initiation and pathogenesis. Although once thought of as immune privileged, the central nervous system (CNS) shows enhanced CD8 T cell activation and clonal expansion across multiple neurodegenerative and inflammatory conditions. However, in most cases, the implicated antigen(s) remain unknown. In this dissertation, different mechanisms of antigen generation in neurodegeneration are explored by deeply profiling human cohorts of myelin oligodendrocyte glycoprotein-associated disease (MOGAD), amyotrophic lateral sclerosis (ALS), and inclusion body myositis (IBM) using high-throughput multiomic antigen screening and in vitro functional assays. MOGAD is a recently characterized antibody-mediated demyelinating disorder of the CNS. We present data demonstrating the occurrence of a high-frequency CD8+ T cell clone capable of recognizing a self-antigen derived from the NMDA-NR1 protein. The presence of activated CD8+ T cells targeting NMDA-NR1 suggests that cell-mediated cytotoxicity may contribute to disease pathogenesis. Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features ALS and 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. Here, we identify “cryptic epitopes”, neoantigens induced by TDP-43 dysfunction, deriving from HDGFL2 and IGLON5 which are recognized by clonally expanded populations of CD8+ T cells in ALS and IBM patients. We demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to the cryptic epitopes and are able to kill TDP-43 deficient astrocytes. Finally, 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 cell and class I antigen presentation pathways. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology.