Role of hybrid peptide specific T cells in diabetes

摘要 尽管进行了多年的研究，但仍不清楚哪些抗原特异性的CD4+T细胞启动了T1D。新的 有证据表明，由胰岛β细胞蛋白融合形成的杂交肽(HP)可能 是T1D中的关键抗原，因为最近的研究发现T1D中有Hp反应的CD4+T细胞 患者和糖尿病小鼠的体外实验。在初步研究中，我们鉴定了幽门螺杆菌特异性的CD4+T细胞 使用新的四聚体试剂，并表明它们可以在小鼠转移模型中引起T1D。 因此，我们假设HPS是关键抗原，对HPS的自身反应启动T1D。 幽门螺杆菌是否会刺激CD4+T细胞启动T1D的决定因素是炎症 初始T细胞受体信号传递期间的背景，特别是I型干扰素(干扰素-I)的时机 曝光。Aim 1将利用不同T1D敏感性的小鼠品系，并评估它们的 幽门螺杆菌特异性细胞的频率和激活表型。我们预测定向混合动力车 多肽特异性细胞将预防并可能逆转T1D，从而证实其致病作用 角色。这项工作的完成还将为杂交肽特异性细胞的作用提供深入的认识 在人类T1D中，我们将评估这些细胞在T1D患者中的频率和表型 以及处于危险中的个人。目的2将检验干扰素-I或病毒感染(S)同时存在的假设 使用TCR信号会导致T1D，而在TCR信号之前暴露干扰素-I会促进Tregs 以及对T1D的保护。最后，我们将使用抗原偶联细胞或 新肽：在正常微生物实验小鼠中阻断MHCII抗体以确定是否 耐受性可以在更接近于 人类。

Summary Despite years of research, it is still unclear which antigen-specific CD4+ T cells initiate T1D. New evidence suggests that hybrid peptides (HP) formed from the fusion of islet β cell proteins may be critical antigens in T1D as recent studies identified HP-reactive CD4+ T cells from T1D patients and diabetic mice in vitro. In preliminary studies, we identified HP-specific CD4+ T cells using novel tetramer reagents, and showed they can cause T1D in mouse transfer models. Thus, we hypothesize that HPs are critical antigens and that autoreactivity to HPs initiates T1D. The deciding factor in whether HP will prime CD4+ T cells to initiate T1D is the inflammatory context during initial T cell receptor signaling, particularly the timing of type I interferon (IFN-I) exposure. Aim 1 will utilize mouse strains of varying T1D susceptibilities, and evaluate their frequency and activation phenotype of HP-specific cells. We predict that targeting hybrid peptide-specific cells will prevent and possibly reverse T1D, thus confirming their pathogenic role. Completion of this work will also provide insight into the role of hybrid peptide-specific cells in human T1D, as we will evaluate the frequency and phenotype of these cells in T1D patients and at-risk individuals. Aim 2 will test the hypothesis that IFN-I or viral infection(s) concurrent with TCR signaling leads to T1D, while IFN-I exposure preceding TCR signaling promotes Tregs and protection from T1D. Finally, we will test tolerance induction using antigen-coupled cells or novel peptide:MHCII blocking antibodies in normal microbial experience mice to determine if tolerance can be induced in a physiological environment more closely resembling that of humans.