MODULATION OF TCR/MHC EXPRESSION AND IMMUNOLOGICAL EFFECTS

这个单位的总体假设是，在个体发育和感染过程中，内吞途径的调节机制在影响TCR和I、II类MHC分子的有效表达方面至关重要。据预测，其中一些调节机制是针对人类细胞的。因此，为了对理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类组织和血液的细胞进行。本单元的具体目标集中在内吞途径如何在免疫反应的发展和刺激过程中控制TCR或MHC分子的表达。每个目标代表着与该项目中至少一名其他研究人员的合作。建议的实验结合了主要研究人员在内吞作用和抗原提呈方面的细胞生物学专业知识，以及其他四名研究人员在研究淋巴和髓系细胞发育、激活和感染方面的专业知识。具体目标如下。目标1将定义TCR在个体发育和激活过程中的调节机制。TCR对抗原刺激的下调是受体介导的内吞作用的信号诱导刺激的功能，这一假设将得到检验。在个体发育和激活过程中，笼蛋白包裹的囊泡在控制TCR表达中的作用将被确定，并建立调控机制。目标2将确定在正常情况下和在HIV感染期间I类MHC的调节机制。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表达的假说将被研究。将确定HIV编码的nef蛋白在这些不同类型的细胞中I类MHC表达的影响，并将分析nef在HIV感染细胞逃避细胞毒细胞识别中的作用。目标3将确定沙眼衣原体感染过程中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表达的减少是由于细菌通过内吞途径改变了II类MHC的运输，这一假说将得到验证。修饰的机制将被确定，感染细胞对T细胞的刺激将被评估为该病原体免疫逃避的机制。

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.