Therapeutic T cell-based vaccination for neurodegenerative disorders: The role of CD4⁺CD25⁺ regulatory T cells

A well-controlled local immune response is needed for recovery from CNS injury, and autoimmune T cells play a key role in mediating this response. Autoimmunity, at least in the context of the CNS, is the body's fighting force against self-derived destructive compounds, and "tolerance to self" (traditionally though mistakenly equated with nonresponsiveness) should be viewed as the ability to tolerate autoimmune responses without developing an autoimmune disease. This physiological repair mechanism is controlled by naturally occurring CD4⁺CD25⁺ regulatory T cells (Treg cells), with an on/off switch regulated by brain-derived compounds. We suggest that ongoing neurodegeneration after acute injuries results from insufficiency of the endogenous fighting force, and chronic neurodegenerative diseases reflect age-related deterioration of the body's two principal regulators: the central nervous system (CNS) and the immune system. If so, then the restoration or boosting of immune function might bridge the gap between such manifestations of CNS-related risk factors and the defensive capacity of the immune system. Boosting of peripheral immunity by the use of weak agonists of CNS self-antigens, might offer a promising potential therapy for different neurodegenerative conditions. This could be accomplished either by vaccination with a universal weak T cell-reactive antigen or with altered peptide ligands of self-antigens, or by weakening the suppressive effect of autoimmunity (e.g., by eliminating Treg cells). T cells that home to the damaged CNS might then help restore local homeostasis by controlling the local microglial response. Because neurodegenerative diseases possess common features (deriving from the local chaos), the same vaccine might protect against several different disorders associated with impaired motor, sensory, cognitive, or mental functions of the brain.