Autoimmune T cell responses in the central nervous system (CNS) play a crucial role in diseases like multiple sclerosis (MS). Recent research highlights two distinct CD4⁺ T cell subsets—those producing interferon-γ (T H1) and interleukin-17 (T H17)—as key mediators of CNS autoimmunity. These subsets influence disease pathology and clinical outcomes. Myelin-specific CD8⁺ T cells also contribute to CNS autoimmunity. This review discusses recent advances in understanding the pathogenic mechanisms, regulation, and interactions of these T cell subsets in CNS autoimmunity. Autoimmune T cells targeting CNS antigens can trigger diseases such as MS, neuromyelitis optica, and acute disseminated encephalomyelitis. MS, the most common, affects over 1 million people globally. It occurs in genetically predisposed individuals after exposure to environmental triggers that activate myelin-specific T cells, allowing them to cross the blood-brain barrier. Reactivation of these T cells by CNS-resident antigen-presenting cells (APCs) recruits innate immune cells, leading to demyelination and axonal damage. MS patients exhibit significant clinical and pathological heterogeneity, suggesting multiple pathways can lead to chronic CNS autoimmunity. The complexity of MS pathology is reflected in diverse clinical symptoms, disease courses, and pathological features. T cell infiltration and reactivation are critical steps in CNS inflammation. T cells cross barriers like the blood-brain and blood-cerebrospinal fluid barriers, entering regions like the subarachnoid space (SAS) and perivascular space. T cell reactivation in the SAS leads to T cell proliferation and recruitment into the perivascular space, initiating inflammation. T cell activation in the SAS also triggers microglial activation and axonal damage, leading to Wallerian degeneration. CD4⁺ T cells, particularly those specific for myelin antigens like MBP and PLP, are primary mediators in EAE models. Their activation depends on MHC class II molecules and involves central tolerance mechanisms. T cells with low avidity for self-antigen can escape central tolerance and become pathogenic. High-avidity T cells can cause severe inflammation in tissues with high MBP concentrations, while low-avidity T cells are deleted in the thymus. CD8⁺ T cells also contribute to CNS autoimmunity, with studies showing their role in EAE and MS. CD8⁺ T cells can be activated in the periphery by APCs, including dendritic cells and macrophages, which present myelin-derived peptides. CD8⁺ T cells can induce demyelinating disease and are involved in epitope spreading. Their role in MS is complex, with some responses being protective and others pathogenic. APCs, including macrophages, dendritic cells, and microglial cells, are crucial for T cell activation and antigen presentationAutoimmune T cell responses in the central nervous system (CNS) play a crucial role in diseases like multiple sclerosis (MS). Recent research highlights two distinct CD4⁺ T cell subsets—those producing interferon-γ (T H1) and interleukin-17 (T H17)—as key mediators of CNS autoimmunity. These subsets influence disease pathology and clinical outcomes. Myelin-specific CD8⁺ T cells also contribute to CNS autoimmunity. This review discusses recent advances in understanding the pathogenic mechanisms, regulation, and interactions of these T cell subsets in CNS autoimmunity. Autoimmune T cells targeting CNS antigens can trigger diseases such as MS, neuromyelitis optica, and acute disseminated encephalomyelitis. MS, the most common, affects over 1 million people globally. It occurs in genetically predisposed individuals after exposure to environmental triggers that activate myelin-specific T cells, allowing them to cross the blood-brain barrier. Reactivation of these T cells by CNS-resident antigen-presenting cells (APCs) recruits innate immune cells, leading to demyelination and axonal damage. MS patients exhibit significant clinical and pathological heterogeneity, suggesting multiple pathways can lead to chronic CNS autoimmunity. The complexity of MS pathology is reflected in diverse clinical symptoms, disease courses, and pathological features. T cell infiltration and reactivation are critical steps in CNS inflammation. T cells cross barriers like the blood-brain and blood-cerebrospinal fluid barriers, entering regions like the subarachnoid space (SAS) and perivascular space. T cell reactivation in the SAS leads to T cell proliferation and recruitment into the perivascular space, initiating inflammation. T cell activation in the SAS also triggers microglial activation and axonal damage, leading to Wallerian degeneration. CD4⁺ T cells, particularly those specific for myelin antigens like MBP and PLP, are primary mediators in EAE models. Their activation depends on MHC class II molecules and involves central tolerance mechanisms. T cells with low avidity for self-antigen can escape central tolerance and become pathogenic. High-avidity T cells can cause severe inflammation in tissues with high MBP concentrations, while low-avidity T cells are deleted in the thymus. CD8⁺ T cells also contribute to CNS autoimmunity, with studies showing their role in EAE and MS. CD8⁺ T cells can be activated in the periphery by APCs, including dendritic cells and macrophages, which present myelin-derived peptides. CD8⁺ T cells can induce demyelinating disease and are involved in epitope spreading. Their role in MS is complex, with some responses being protective and others pathogenic. APCs, including macrophages, dendritic cells, and microglial cells, are crucial for T cell activation and antigen presentation