REGULATION OF SELF ANTIGEN PRESENTATION BY MHC CLASS II

抗原提呈细胞(APC)上的MHC II类分子结合自身和 外源多肽在细胞内并在细胞表面展示 以供抗原特异性的CD4+T细胞识别。展示自我 由MHC-II类分子产生的多肽在这两个正常人群中都发挥着重要作用 以及免疫系统的异常功能。然而，人们对此知之甚少 关于这些自体多肽或正常细胞的性质和起源 它们在体内显示的类型。我假设过 通过炎症刺激或病毒感染激活或应激APC 将改变APC显示的自体多肽的密度和多样性， 并导致外周自我耐受性的破坏。为了方便 对自身抗原提呈的研究，我开发了一种独特的T细胞 12个不同的天然加工的II类结合自身的细胞 来源于跨膜或胞质蛋白的多肽。至 更好地理解APC展示自我的机制 结合MHC II类分子的多肽，我提出了3个靶点。在AIM 1，我将检验用细胞因子、细菌 脂蛋白或细胞应激改变自体II类多肽的排列 正常小鼠体外APC所显示的复合体。随后，发生了变化 在抗原呈递中将被抑制物操纵 细胞内通路。在目标2中，我将测试假设 不同的自身抗原被蛋白质降解并加载到 第二类分子在内吞途径的不同部分，作为一个 它们的原始蜂窝位置的功能。这些研究将涉及 亚细胞分离技术。在目标3中，我将测试 假设体内的病毒感染导致了一系列 正常APC所显示的自身多肽。我将使用体内模型 小鼠皮肤感染单纯疱疹病毒，可以进行比较 淋巴样PAC和表皮PAC。这些研究将研究这些影响 炎症和病毒感染的发病机制的展示 通过正常的体外APC获得自体多肽，并将为 感染性病原体和自身免疫T细胞反应之间的联系。

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.