Regulatory T cells in human autoimmune diseases

In the most simplistic terms, immune tolerance can be envisioned as a balance with autoreactive cells that arise naturally in all individuals on one side and regulatory mechanisms designed to counter those autoreactive processes on the other. A tilt of the balance toward the autoreactive side, either by increasing the number or function of autoreactive cells or by diminishing regulatory mechanisms, is manifested as autoimmunity. In contrast, tilting of the balance toward increased regulation could conceivably cause immunodeficiency. Regulatory T cells (T-REG), and particularly the naturally arising CD4(+)CD25(+)subset of T-REG cells, provide a substantial component of the autoimmune counterbalance. The identification of forkhead box P3 (FOXP3) as a critical determinant of CD4(+)CD25(+)T(REG) development and function has provided new opportunities and generated expanded interest in studying the delicate balance between autoimmunity and regulatory mechanisms in human autoimmune diseases. Identification of both human and mouse syndromes in which FOXP3 is mutated, and consequently CD4(+)CD25(+) T-REG cells are absent, has led to a rapid accumulation of knowledge regarding T-REG development and function over the past 5 years. The recent development of antibody reagents to specifically identify CD4(+)CD25(+) T-REG cells by their FOXP3 expression has provided new tools to identify these elusive cells and investigate their role in human disease. This review will focus on the current state of knowledge regarding the role of T-REG in human autoimmune diseases and on specific human immunodeficiencies that provide interesting models of autoimmunity.