Autoimmunity on alert: Naturally occurring regulatory CD4⁺CD25⁺ T cells as part of the evolutionary compromise between a 'need' and a 'risk'

Autoimmunity, at least in the central nervous system (CNS), is not only an outcome of immune system malfunction, but is the body's own protective mechanism against destructive self-compounds. Likewise, the naturally occurring regulatory CD4⁺CD25⁺ T cells have a physiological function, and are not merely an evolutionary adaptation to suppress self-reactive T-cell clones that escaped deletion in the thymus. We postulate that the regulatory T (Tr) cells are the product of an evolutionary compromise between the need for autoimmunity on alert for tissue maintenance and the need to control autoimmunity to avoid autoimmune disease. In the event of an insult to the CNS, the balance between self-reactive (effector) T cells and Tr cells determines the time of onset, the intensity and the duration of the autoimmune response. This response might thus represent an adaptive mechanism, which is optimal for day-to-day maintenance, but insufficient in extreme cases of CNS damage or failure of regulation. Downregulation or upregulation of CD4⁺CD25⁺ Tr cells might be a way to achieve better protection from neurodegenerative conditions induced by self-destruction or avoid autoimmune inflammatory disease development, respectively.