Checkpoints and Autoimmune Homeostasis in T1D

自身反应性的CD4+T细胞在外周血中的出现频率很低，通常具有低的抗原亲和力， 并对多种自身抗原表现出反应性。然而，它们是自身免疫的核心决定因素， 不仅指导免疫反应的特异性和大小，而且还关键地参与平衡 疾病进展和调控之间的关系。我们建议利用最近在几个领域取得的进展。 多聚体技术、T1D预测、细胞微阵列和人性化的小鼠模型 开发与T1D易感性、疾病和保护相关的胰岛抗原反应性T细胞的概况。 在目标1中，人类白细胞抗原II类四聚体(针对6个胰岛抗原)和I类四聚体(针对两个胰岛抗原)将是 与流式细胞仪技术一起用于比较特征性良好的T细胞特征 人类有患T1D或进展性疾病的风险；在目标2中，我们将分析 与T1D相关的一种重要表型，即低亲和力自身反应的性质 CD4+T细胞。为此目的创建的部分人性化的小鼠模型将使详细的评估成为可能 它的激活和寻的特性。在目标3中，旨在翻译研究的新技术 将开发更敏感和更快速的临床测试技术，以促进T细胞图谱的形成 变成一种更有用的临床研究工具。这些研究将与《公约》的其他内容紧密结合。 UCHSC和其他地点的自身免疫合作小组以及由此衍生的资源 该项目也将传播到其他地点。

Autoreactive CD4+ T cells are present at low frequency in peripheral blood, often with low antigen avidity, and show reactivity to multiple autoantigens. Nevertheless, they are central determinants of autoimmunity, guiding not only specificity and magnitude of immune responses, but also critically involved in the balance between disease progression and regulation. We propose to exploit recent advances in several areas¿ multimer technology, T1D prediction, cellular microarrays, and humanized mouse models¿in order to develop profiles for islet antigen-reactive T cells associated with T1D susceptibility, disease, and protection. In Aim 1, HLA class II tetramers (for six islet antigens) and class I tetramers (for two islet antigens) will be used together with flow cytometry techniques to compare T cell characteristics among well-characterized human subjects at risk for T1D or with progressive disease; In Aim 2, we will analyze the functional properties of one of the important phenotypes associated with T1D¿namely, the low avidity autoreactive CD4+ T cells. A partially humanized mouse model created for this purpose will enable a detailed evaluation of the activation and homing properties. In Aim 3, new technologies designed to translate research techniques into more sensitive and rapid clinical tests will be developed, in order to advance T cell profiling into a more useful clinical research tool. These studies will be closely integrated with other elements of the Autoimmunity Cooperative Group, both at UCHSC and at other sites, and the resources derived in this project will be disseminated to the other sites, as well.