Autoreactive T cell responses have a crucial role in central nervous system (CNS) diseases such as multiple sclerosis. Recent data indicate that CNS autoimmunity can be mediated by two distinct lineages of CD4 + T cells that are defined by the production of either interferon-γ or interleukin-17. The activity of these CD4 + T cell subsets within the CNS influences the pathology and clinical course of disease. New animal models show that myelin-specific CD8 + T cells can also mediate CNS autoimmunity. This Review focuses on recent progress in delineating the pathogenic mechanisms, regulation and interplay between these different T cell subsets in CNS autoimmunity.Autoimmune T cell responses directed against antigens that are derived from the central nervous system (CNS) are thought to trigger several diseases, including multiple sclerosis, neuromyelitis optica and acute disseminated encephalomyelitis. Multiple sclerosis is the most common of these diseases, affecting more than one million people worldwide 1 . Multiple sclerosis is thought to occur in genetically predisposed individuals following exposure to an environmental trigger that activates myelin-specific T cells, which allows the T cells to cross the blood-brain barrier. Reactivation of the T cells by CNS-resident antigen-presenting cells (APCs) that present myelin antigens triggers the recruitment of innate immune cells, which have important roles in mediating demyelination and axonal damage. Immune cell infiltrates and plaques of demyelination in the brain and spinal cord are hallmark features of multiple sclerosis; however, extensive heterogeneity in the clinical symptoms, disease course and detailed pathological features is seen among patients (BOX 1). This suggests that many pathways involving distinct effector mechanisms can lead to chronic autoimmune disease in the CNS 2 . Box 1 The complexity of autoimmune diseases affecting the CNSThe diverse clinical and pathological outcomes seen in patients with multiple sclerosis suggest that T cell responses in the central nervous system (CNS) are complex. Clinical signs that are associated with multiple sclerosis include ataxia, loss of coordination, hyperreflexia, spasticity, visual and sensory impairment, fatigue and cognitive difficulties 1 . However, the severity, frequency, specific clinical symptoms and CNS pathology vary greatly among patients with this disease, and the basis for this variation is not understood. Approximately 85% of patients with multiple sclerosis have a relapsingremitting form of the disease, which usually converts over years into a progressive disease that is characterized by severe neurological deterioration. 10-15% of patients with multiple sclerosis follow a primary progressive disease course in which continuous neurological deterioration occurs following the initial episode. A small percentage of patients develop severe disease that leads to extreme disability or death after only months. The reasons underlying these different disease courses are not clear. Most patient...

Multiple sclerosis is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by a wide range of clinical signs 1 . The location of lesions in the CNS is variable and is a crucial determinant of clinical outcome. Multiple sclerosis is believed to be mediated by myelinspecific T cells, but the mechanisms that determine where T cells initiate inflammation are unknown. Differences in lesion distribution have been linked to the HLA complex, suggesting that T cell specificity influences sites of inflammation2. We demonstrate that T cells that are specific for different myelin epitopes generate populations characterized by different T helper type 17 (T H 17) to T helper type 1 (T H 1) ratios depending on the functional avidity of interactions between TCR and peptide-MHC complexes. Notably, the T H 17:T H 1 ratio of infiltrating T cells determines where inflammation occurs in the CNS. Myelin-specific T cells infiltrate the meninges throughout the CNS, regardless of the T H 17:T H 1 ratio. However, T cell infiltration and inflammation in the brain parenchyma occurs only when T H 17 cells outnumber T H 1 cells and trigger a disproportionate increase in interleukin-17 expression in the brain. In contrast, T cells showing a wide range of T H 17:T H 1 ratios induce spinal cord parenchymal inflammation. These findings reveal critical differences in the regulation of inflammation in the brain and spinal cord.Experimental autoimmune encephalomyelitis (EAE) is an animal model that shows many similarities to multiple sclerosis3. However, rodent EAE differs from multiple sclerosis by manifesting as ascending flaccid paralysis, reflecting unexplained preferential targeting of inflammation to the spinal cord (described as classic EAE). In a small number of antigenspecific models, brain inflammation occurs (described as atypical EAE)4 -8. Interferon-γ (IFN-γ) deficiency also causes certain myelin-specific T cells to preferentially induce brain

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This protocol details a method to actively induce experimental allergic encephalomyelitis (EAE), a widely used animal model for studies of multiple sclerosis. EAE is induced by stimulating T-cell-mediated immunity to myelin antigens. Active induction of EAE is accomplished by immunization with myelin antigens emulsified in adjuvant. This protocol focuses on induction of EAE in mice; however, the same principles apply to EAE induction in other species. EAE in rodents is manifested typically as ascending flaccid paralysis with inflammation targeting the spinal cord. However, more diverse clinical signs can occur in certain strain/antigen combinations in rodents and in other species, reflecting increased inflammation in the brain.