Autoimmune T cell responses in the central nervous system

Multiple sclerosis is thought to be mediated by autoimmune T cell responses directed against antigens derived from the central nervous system (CNS). The clinical course, symptoms and pathology seen in patients with multiple sclerosis is heterogeneous, suggesting that multiple sclerosis in different patients may result from distinct pathogenic pathways.Autoimmune disease in the CNS occurs when self-reactive T cells specific for CNS antigens are activated in the periphery, either by presentation of the self antigen in the CNS-draining (cervical) lymph nodes or by a molecular mimic of the self antigen. Unlike naive T cells, activated T cells can cross the blood–cerebrospinal fluid (CSF) or blood–brain barrier. Activated T cells are believed to initially cross the blood–CSF barrier and enter the subarachnoid space, where their reactivation facilitates activation of the vascular endothelium and subsequent T cell entry into the perivascular space.The myelin-specific CD4+ T cells that mediate CNS autoimmunity in animal models are usually T cells that circulate in the periphery because they escaped central tolerance owing to low avidity for their cognate antigen.Both CD4+ T helper 1 (TH1) cells, characterized by interferon-γ (IFNγ) secretion, and TH17 cells, characterized by interleukin-17 (IL-17) secretion, can induce CNS autoimmune disease. The interplay between these T cell subsets as well as their interaction with other cells that reside within the CNS is poorly understood but is likely to have an important role in shaping the inflammatory response in different locations within the CNS.During inflammation there are many cell types that can present antigen to CD4+ T cells; the relative contribution and activation state of these different antigen-presenting cells strongly influences the effector function and survival of T cells in the CNS.CD8+ T cells exhibit more evidence of antigen-driven expansion in the CNS of patients with multiple sclerosis, and myelin-specific CD8+ T cells are highly pathogenic in experimental autoimmune encephalomyelitis. However, in addition to CD4+ regulatory T cells, several different types of regulatory CD8+ T cells have been described that may be important in the pathology of multiple sclerosis.Despite the fact that T cells are believed to be the primary effector cells in the pathology of multiple sclerosis, depletion of B cells is a promising therapeutic treatment for patients with multiple sclerosis. It is not yet clear whether the beneficial effect of this therapy is due to disruption of the antigen-presenting function of B cells or their ability to produce antibodies.