Abstract
Autoreactive CD8(+) regulatory T cells (Tregs) play important roles as modulators of immune responses against self, and numerical and functional defects in CD8(+) Tregs have been linked to autoimmunity. Several subsets of CD8(+) Tregs have been described. However, the origin of these T cells and how they participate in the natural progression of autoimmunity remain poorly defined. We discuss several lines of evidence suggesting that the autoimmune process itself promotes the development of autoregulatory CD8(+) T cells. We posit that chronic autoantigenic exposure fosters the differentiation of non-pathogenic autoreactive CD8(+) T cells into antigen-experienced, memory-like autoregulatory T cells, to generate a "negative feedback" regulatory loop capable of countering pathogenic autoreactive effectors. This hypothesis predicts that approaches capable of boosting autoregulatory T cell memory will be able to blunt autoimmunity without compromising systemic immunity.