Too dangerous to ignore: Self-tolerance and the control of ignorant autoreactive T cells

Self-reactive T cells often escape thymic negative selection and are released into the periphery. While many of these T cells are tolerized by peripheral deletion or anergy, a proportion persists in a naïve (or ignorant) state. Self-ignorant T cells are probably one of the greatest threats to the maintenance of self-tolerance, as inadvertent activation of these cells may provoke autoimmune pathology. Nevertheless, despite the presence of self-ignorant T cells within most individuals, the majority of people fail to develop autoimmunity. The means by which self-ignorant T cells are silenced by the immune system remains a major issue within the tolerance field and it has received surprisingly little attention within the literature. In this review, we first summarize the factors that allow such cells to persist in a self-ignorant state, with a particular focus on the role of self-antigen dose. We next consider the conditions under which such self-reactive cells may become activated and speculate on how the immune system is able to prevent such cells from precipitating autoimmune disease.