REGULATION OF SELF ANTIGEN PRESENTATION BY MHC CLASS II

抗原呈递细胞（APC）上的MHC II类分子结合自身， 并将它们展示在细胞表面 用于抗原特异性CD4+T细胞的识别。自我展示 MHC II类分子的肽在正常人和正常人中都很重要。 以及免疫系统功能异常。然而， 关于这些自身肽的性质和起源，或者正常细胞 它们在体内展示的类型。我假设 通过炎症刺激或病毒感染激活或应激APC 将改变APC展示的自身肽的密度和多样性， 并导致外周自身耐受性的破坏。方便 为了研究自身抗原呈递，我开发了一套独特的测试方法 对12种不同的自然加工的II类结合的自身 衍生自跨膜蛋白或胞质蛋白的肽。到 更好地理解APC显示自我的机制 结合MHC II类分子的多肽，我提出了3个目标。在Aim中 1，我将检验用细胞因子、细菌和细胞因子激活的假设， LPS或细胞应激改变自身肽II类的排列 通过正常离体鼠APC展示的复合物。随后，变化 在抗原呈递中，将用以下抑制剂操纵： 细胞内途径在目标2中，我将检验以下假设： 不同的自身抗原被蛋白水解降解并装载到 II类分子在内吞途径的不同部分，作为 其原始蜂窝位置的功能。这些研究将涉及 亚细胞分级分离技术。在目标3中，我将测试 假设体内病毒感染导致一系列的变化， 正常APC展示的自身肽。我将使用体内模型， 单纯疱疹病毒引起的小鼠皮肤感染， 淋巴和表皮PAC的感染这些研究将研究 炎症和病毒感染的发病机制的显示 自身肽的正常离体APC，并将提供一个基本原理， 感染因子与自身免疫性T细胞应答之间的联系。

MHC class II molecules on antigen presenting cells (APC) bind self and foreign peptides intracellularly and display them on the cell surface for recognition by antigen-specific CD4+T cells. Display of self peptides by MHC class II molecules figures importantly in both normal and abnormal functioning of the immune system. However, little is known about the nature and origin of these self peptides, or the normal cell types on which they are displayed in vivo. I have hypothesized that activation or stress of APC via inflammatory stimuli or viral infection will alter the density and diversity of self peptides displayed by APC, and lead to disruption of peripheral self tolerance. To facilitate the study of self antigen presentation, I have developed a unique panel of T cells specific for 12 distinct naturally processed class II-bound self peptides derived from either transmembrane or cytosolic proteins. To gain a better understanding of the mechanism by which APC display self peptides bound to MHC class II molecules, I have proposed 3 aims. In Aim 1, I will test the hypothesis that activation with cytokines, bacterial LPS or cellular stress changes the array of self peptide class II complexes displayed by normal ex vivo murine APC. Subsequently, changes in antigen presentation will be manipulated with inhibitors of intracellular pathways. In Aim 2, I will test the hypothesis that distinct self antigens are proteolytically degraded and loaded onto class II molecules in different parts of the endocytic pathway, as a function of their original cellular location. These studies will involve subcellular fractionation techniques. In Aim 3, I will test the hypothesis that in vivo viral infection leads to changes in the array of self peptides displayed by normal APC. I will use an in vivo model of murine skin infection by Herpes Simplex Virus that will allow comparison of both lymphoid and epidermal PAC. These studies will study the effects of inflammation and the pathogenesis of viral infection on the display of self peptides by normal ex vivo APC, and will provide a rationale for linkage between infectious agents and autoimmune T cell responses.