Immune Deviation-the Third Dimension of Nondeletional T Cell Tolerance

The description of "horror autotoxicus" by Ehrlich & Morgenroth (1957) and of the mutual tolerance of dizygotic cattle twins by Owen (1945) initiated the concept of tolerance of self antigens. Based on these and other experiments, Burnet and Fenner (1949) defined tolerance as "non-reactivity against self". However, since that time it has become evident that tolerance may be secondary to several unrelated mechanisms and today tolerance may be best defined as "a physiologic state in which the immune system does not react destructively against the organism that harbors it". Conversely, autoimmunity is best defined as a situation where tolerance is abolished and the immune system reacts destructively against itself. In spite of the relative explosion of knowledge in the past decade, which has included elucidation of the structure of the T cell receptor (TCR), the identification of numerous cytokines, and the creation of transgenic and knockout animals, the relationship between tolerance and autoimmunity remains a challenging problem of clinical and fundamental immunology. Studies in several mouse models involving superantigens or transgenic TCR specific for self- or neoantigens have clearly shown that T cells with high affinity for self antigens are normally deleted during early stages of T cell development in the thymus. Thus, in male C57BL/6 mice with a transgenic TCR specific for H-Y, autoreactive T cells are almost completely deleted and autoimmunity has not been described in this animal model. Similarly, in most of the other animal models potentially autoreactive T cells are deleted in the thymus. Although T cells can even be deleted in the periphery, not all potentially autoreactive T cells are eliminated during T cell development and there is little doubt that self-reactive T cells are responsible for initiation of autoimmunity and autoimmune disease. Thus, autoreactive T cells directed against peptides derived from tissue specific antigens such as myelin basic protein (MBP) as well as T cells directed against complexes of self peptides present in association with major histocompatibility complex (MHC) class II antigens on professional antigen presenting cells (APC) can easily be generated in vitro from healthy donors or normal animals. However, the origin, development, differentiation and natural specificity of autoreactive T cells under physiological conditions remain enigmatic. In any case, pathways for the induction of nondeletional cell tolerance i