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

免疫系统的基本要求是对自身抗原具有耐受性，同时对外来抗原具有完全反应性。免疫系统消除或沉默针对自身抗原的T细胞的能力对于管理这项任务和预防自身免疫至关重要。然而，T细胞介导的自身免疫性疾病如1型糖尿病和多发性硬化症频繁发生。这就提出了一个问题，即有害的自身反应细胞如何逃脱消除。一些罕见的自身免疫病例与导致自身反应性T细胞消除或沉默缺陷的突变有关，但对于大多数病例，没有描述过此类缺陷。我们最近观察到，免疫系统有效地消除了对自身抗原反应强烈的细胞，但它通常不能消除与自身抗原反应弱的细胞，并且在激活时，这些低亲合力T细胞可引起自身免疫。因此，具有自身免疫潜能的T细胞是正常T细胞库的一部分。由于这些细胞在健康个体中是静止的，我们现在建议研究通常控制或抑制其激活的机制。此外，我们还计划研究这些T细胞是如何被招募来引起自身免疫的。这些研究将提高我们对自身免疫性疾病的理解，并将为如何利用低亲和力抗自身T细胞进行肿瘤免疫提供重要信息。

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.