Autoimmunity caused by T cells recognizing tissue restricted antigens with low avidity

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A fundamental requirement of the immune systems is to be tolerant to self-antigens while being fully reactive to foreign antigens. The ability of the immune system to eliminate or silence T cells directed against self-antigens is crucial for managing this task and for preventing autoimmunity. However, T cell mediated autoimmune disorders such as type 1 diabetes and multiple sclerosis occur frequently. This raises the question as to how harmful autoreactive cells escape elimination. Some rare cases of autoimmunity are linked to mutations resulting in defective elimination or silencing of autoreactive T cells, but for the majority of cases no such defects have been described. We recently observed that the immune system efficiently eliminates cells responding strongly to self-antigens but that it routinely fails to eliminate cells that are weakly reactive with self-antigens and that upon activation these low avidity T cells can cause autoimmunity. Thus, T cells with autoimmune potential are part of the normal T cell repertoire. As these cells are quiescent in healthy individuals, we now propose to investigate mechanisms that normally control or suppress their activation. In addition we plan to study how these T cells are recruited to cause autoimmunity. The studies will improve our understanding of autoimmune disease and will provide vital information on how to utilize low avidity anti-self T cells for tumor immunity.