Dual TCR T cells in thymic selection and autoimmunity

描述（由申请人提供）：自身免疫性疾病是常见的，当免疫耐受失败时就会出现。适应性免疫系统的细胞表达多种抗原受体，使免疫系统能够对广泛的潜在病原体作出反应。然而，其抗原受体识别自身抗原的T细胞和B细胞也存在于此库中。多种免疫耐受模式的作用是消除、修饰或抑制这种潜在的自身反应性淋巴细胞。等位基因排斥是免疫耐受的基本机制，确保大多数成熟T细胞仅表达单一抗原受体特异性。然而，等位基因的排除是不完善的，表达两种有效重排TCR？或细胞?在老鼠和人类身上都能找到这种链。双TCR T细胞对免疫耐受构成两种主要的假设风险：这种细胞可能对克隆缺失不太敏感，或者它们可能通过一个TCR识别外源肽：MHC复合物而被激活，然后通过另一个（自身反应性）TCR激发自身免疫。因为细胞?等位基因排斥是如此严格，先前关于双TCR表达在自身免疫中的作用的研究主要集中在双TCR？并得出结论，在几种自身免疫小鼠模型中，双TCR表达不是疾病发展所必需的。双TCR的可能贡献？表达尚未被探索。我们的初步研究表明，不完全TCR？等位基因排斥可导致自身免疫。双TCR的表达？（或双TCR?）链允许自身反应性TCR转基因T细胞逃避克隆缺失，最终导致自发性自身免疫性关节炎。这一意想不到的发现重新开启了双重TCR表达允许自身反应性T细胞逃避克隆缺失并引发自身免疫的可能性。该项目的目标是在广泛使用的小鼠模型中确定双TCR表达是否有助于自身免疫性疾病的发病机制。重要的是，每种模型都涉及具有不同T细胞库的小鼠，而不是转基因编码的tcr。我们建议使用TCR?/TCR？无法产生双TCR T细胞的半合子小鼠，以确定双TCR T细胞是否参与实验性自身免疫性脑脊髓炎和I型糖尿病的发病机制。这些研究有望以明确的方式解决不完全等位基因排斥和由此产生的双TCR表达是否有助于自身免疫性疾病的发展。此外，这些研究有望为未来探索双tcr在人类自身免疫性疾病中的作用奠定基础。

DESCRIPTION (provided by applicant): Autoimmune diseases are common and arise when immunological tolerance fails. Cells of the adaptive immune system express a diverse repertoire of antigen receptors, enabling the immune system to respond to a wide range of potential pathogens. However, T and B cells whose antigen receptors recognize self antigens also exist within this repertoire. Multiple modes of immunological tolerance act to eliminate, modify, or restrain such potentially autoreactive lymphocytes. Allelic exclusion is a fundamental mechanism of immunological tolerance, acting to ensure that most mature T cells express only a single antigen receptor specificity. Allelic exclusion is imperfect, however, and T cells that express two productively rearranged TCR? or TCR? chains can be found in both mice and humans. Dual TCR T cells pose two main hypothetical risks to immunological tolerance: such cells might be less susceptible to clonal deletion or they could be activated by recognition of foreign peptide:MHC complexes through one TCR, then provoke autoimmunity through the other (autoreactive) TCR. Because TCR? allelic exclusion is so stringent, prior studies of the role of dual TCR expression in autoimmunity have focused on dual TCR? expression and have concluded that dual TCR expression is not necessary for disease development in several mouse models of autoimmunity. A possible contribution of dual TCR? expression has not been explored. Our preliminary studies demonstrated that incomplete TCR? allelic exclusion can lead to autoimmunity. Expression of dual TCR? (or dual TCR?) chains allowed autoreactive TCR transgenic T cells to escape clonal deletion, culminating in spontaneous autoimmune arthritis. This unexpected finding re-opens the possibility that dual TCR expression can allow autoreactive T cells to escape clonal deletion and provoke autoimmunity. The goal of the proposed project is to determine whether dual TCR expression contributes to autoimmune disease pathogenesis in widely-used mouse models. Importantly, each of these models involves mice with diverse T cell repertoires rather than transgene-encoded TCRs. We propose to use TCR?/TCR? hemizygous mice which are unable to generate dual TCR T cells to determine whether dual TCR T cells are involved in the pathogenesis of experimental autoimmune encephalomyelitis and type I diabetes. These studies are expected to address in a definitive fashion whether incomplete allelic exclusion and the resulting dual TCR expression can contribute to the development of autoimmune diseases. In addition, the studies are expected to form the basis for future work exploring a role for dual TCRs in human autoimmune diseases. PUBLIC HEALTH RELEVANCE: Immunological tolerance refers to the capacity of the immune system not to react to self tissues; autoimmune diseases arise when immunological tolerance breaks down. We have found that expression of two different T cell receptors (TCRs) rather the just one, as is customary, allows autoreactive T cells to escape immunological tolerance and to cause autoimmune disease in an engineered mouse model. This study focuses on determining whether dual TCR expression contributes to autoimmune diseases in normal mice, as a bridge to future studies evaluating the role of dual TCR expression in human autoimmune diseases.