T regulatory cells play an important role in regulating T-cell responses to self-antigens and control autoimmunity and autoimmune disease. Anti-ergotypic T cells are a subset of such regulatory T cells that respond to activation markers, ergotopes, expressed on other activated T cells. Anti-ergotypic T cells do not respond to nonactivated T cells. Ergotopes include the a-chain of the IL-2 receptor (CD25). Anti-ergotypic T cells were found to downregulate experimental diseases such as experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA). Anti-ergotypic T cells are present in humans and are activated after T-cell vaccination. Here we review anti-ergotypic T cells in animal models and in humans and contrast anti-ergotypic T cells with other regulatory T-cell subsets.