Role of hybrid peptide specific T cells in diabetes

总结 尽管多年的研究，它仍然是不清楚的抗原特异性CD 4 + T细胞启动T1 D。新 有证据表明，由胰岛β细胞蛋白融合形成的杂合肽（HP）可能 是T1 D中的关键抗原，因为最近的研究从T1 D中鉴定出HP反应性CD 4 + T细胞 患者和糖尿病小鼠体外。在初步研究中，我们鉴定了HP特异性CD 4 + 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T1 D。 因此，我们假设HP是关键抗原，对HP的自身反应性启动T1 D。 HP是否会引发CD 4 + T细胞启动T1 D的决定因素是炎症反应。 在初始T细胞受体信号传导过程中的背景，特别是I型干扰素（IFN-I）的时机 exposure.目的1将利用不同T1 D易感性的小鼠品系，并评估其 频率和HP特异性细胞的活化表型。我们预测目标混合体 肽特异性细胞将预防并可能逆转T1 D，从而证实其致病性。 作用这项工作的完成也将提供深入了解杂交肽特异性细胞的作用 因为我们将评估这些细胞在T1 D患者中的频率和表型， 和高危人群目的2将检验IFN-I或病毒感染并发 TCR信号传导导致T1 D，而TCR信号传导之前的IFN-1暴露促进T1 D 保护T1 D。最后，我们将使用抗原偶联细胞或 新肽：MHCII阻断抗体在正常微生物经验小鼠中，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.