Levels of peripheral T cell tolerance.

The immune system is an adaptive defense system capable of specifically recognizing and eliminating an apparently limitless variety of foreign invaders. This highly specific response is provided by T and B lymphocytes. The enormous diversity of the antigen-specific receptors on these cells is generated by random rearrangement of the respective genes. The key challenge of such a defense system is to have as broad a T and B cell repertoire as possible in the absence of autoreactivity. This review summarizes mechanisms of peripheral T cell tolerance induction seen in various animal models. There is increasing evidence that tolerance to tissue-specific antigens can be induced by dendritic cells in the regional lymph nodes as well as by parenchymal cells like keratinocytes and hepatocytes in the respective tissues. Furthermore, tolerance induction should no longer only be viewed as prevention of T cell activation, as in certain systems activation of autoreactive T cells is insufficient to cause tissue damage. Thus, several tolerance mechanisms are operating in parallel under physiological conditions. With increasing knowledge of the molecular basis we will learn which mechanism is most suitable for therapeutic intervention.