The central nervous system (CNS) is traditionally considered as an immunoprivileged site, where excessive immune responses can cause irreversible damage, as observed in autoimmune diseases such as multiple sclerosis (MS). Cytotoxic CD8⁺ T cells are crucial for pathogen clearance. However, they can also recognize self-antigens, leading to tissue damage and resulting in autoimmunity. CD8⁺ T cells undergo activation and differentiation as both extrinsic and intrinsic factors shape their transcriptional and epigenetic landscapes, determining their fate. Understanding how these factors influence CD8⁺ T-cell differentiation is essential to identifying conditions that promote autoreactivity. Using a model of chronic CNS autoimmunity, we investigated the role of both extrinsic and intrinsic factors in shaping CD8⁺ T-cell responses. We focused on the alarmin IL-33 as an extrinsic factor while intrinsic factors included the transcription factors (TFs) T-BET and ZBTB25. We found that oligodendrocyte-derived IL-33 plays a critical role in locally regulating the pathogenicity of self-reactive CD8⁺ T cells. Selective ablation of IL-33 from neo-self-antigen-expressing oligodendrocytes attenuated CNS disease, leading to less persistent self-reactive CD8⁺ T cells and impaired generation of TCF-1^low effector cells. IL-33 shaped the transcriptional landscape of self-reactive CD8⁺ T cells by modulating effector, exhaustion, circulating, and tissue-residency gene expression signatures. Furthermore, therapeutic IL-33 blockade through locally administered somatic gene therapy reduced T-cell infiltration and improved disease outcome. In the second part, we characterized how T-BET and ZBTB25 TFs regulate the differentiation of self-reactive CD8⁺ T cells withing the CNS. We found that during the acute phase, both limit early memory commitment and CNS accumulation. In contrast, in the chronic phase, ZBTB25 appears essential supports of CD8⁺ T-cell persistence in the CNS, while T-BET constrains the establishment of CNS-resident CD8⁺ T cells, which can sustain local disease progression. Altogether, our findings reveal two complementary axes regulating CNS autoimmunity: an extrinsic tissue-derived cue (IL-33) and intrinsic transcriptional regulators (T-BET and ZBTB25), providing mechanistic insight into disease progression and potential therapeutic strategies to overcome treatment resistance in progressive forms of the disease.