MODULATION OF TCR/MHC EXPRESSION AND IMMUNOLOGICAL EFFECTS

本单元的总体假设是，在个体发生和感染过程中，内吞途径的调控机制对影响TCR和I类和II类MHC分子的有效表达至关重要。据预测，其中一些调节机制对人类细胞是特异性的。因此，为了对了解人类疾病产生最大的影响，这些关于内吞途径免疫功能的研究将使用来自人体组织和血液的细胞进行。本单元的具体目的侧重于内吞途径如何控制TCR或MHC分子在免疫反应的发展和刺激过程中的表达。每个目标都代表了与该计划中至少一名其他研究者的合作。这些实验将主要研究人员在细胞内吞作用和抗原呈递方面的专业知识与其他四位研究人员在淋巴细胞和髓细胞发育、活化和感染方面的专业知识结合起来。具体目的如下。目的1将定义TCR在个体发生和激活过程中的调节机制。关于抗原刺激下TCR下调是信号诱导刺激受体介导的内吞作用的假设将被验证。在个体发生和激活过程中，网格蛋白包被囊泡在控制TCR表达中的作用将被明确，并建立其调控机制。目标2将定义在正常条件下和HIV感染期间I类MHC调节的机制。我们将研究不同的内吞信号调节胸腺细胞、胸腺上皮细胞和淋巴细胞表面I类MHC表达的假设。hiv编码的nef蛋白在这些不同细胞类型中对I类MHC表达的影响将被定义，nef在hiv感染细胞逃避细胞毒性细胞识别中的作用将被分析。Aim 3将定义沙眼衣原体感染期间II类MHC调节的机制和免疫学后果。衣原体感染细胞中II类MHC表达减少是由于细菌诱导的II类MHC通过内噬途径转运的修饰，这一假设将得到验证。修饰的机制将被定义，并通过感染细胞刺激T细胞来评估该病原体的免疫逃避机制。

The overall hypothesis of this unit is that regulatory mechanisms of the endocytic pathway are critical in influencing the effective expression of TCR and class I and II MHC molecules during ontogeny and infection. Some of these regulatory mechanisms are predicted to be specific to human cells. Therefore, to have the greatest impact on understanding human disease, these studies on the immune function of the endocytic pathway will be carried out using cells derived from human tissue and blood. The specific aims of this unit focuses on how the endocytic pathway controls expression of either TCR or MHC molecules during the development and stimulation of an immune response. Each aim represents a collaboration with at least one other investigator in the program. The experiments proposed draw upon a combination of principal investigators expertise in the cell biology of endocytosis and antigen presentation with the expertise of the other four investigators in studying lymphoid and myeloid cell development, activation, and infection. The specific aims are as follows. Aim 1 will define mechanisms of TCR modulation during ontogeny and activation. The hypothesis that TCR down-regulation upon antigenic stimulation is a function of signaling-induced stimulation of receptor-mediated endocytosis will be tested. The role of clathrin-coated vesicles in controlling expression of TCR during ontogeny and activation will be defined and the regulatory mechanisms established. Aim 2 will define mechanisms of class I MHC modulation under normal conditions and during HIV infection. The hypothesis that differential endocytic signals regulate class I MHC expression on the surface of thymocytes, thymic epithelial cells and lymphocytes will be investigated. The effect of expression of the HIV-encoded nef protein in class I MHC expression in these different cell types will be defined and the role of nef in evasion of cytotoxic cell recognition by HIV-infect cells will be analyzed Aim 3 will define mechanisms and immunological consequences of class II MHC modulation during infection by Chlamydia trachomatis. The hypothesis that the reduction in class II MHC expression in Chlamydia-infected cells results from bacteria-induced modification of class II MHC transport through the endocytic pathway will be verified. The mechanism of modification will be defined and T cell stimulation by infected cells will be evaluated as a mechanism for immune evasion by this pathogen.