T CELLS IN GRANULOMATOUS IMMUNE RESPONSES

对感染因子的早期免疫通常涉及对少数免疫显性表位的非常明确的T细胞应答。然而，抗原特异性在慢性炎症部位T细胞积聚中的作用尚不清楚。本应用的主要目的是了解抗原和T细胞受体特异性在慢性肉芽肿炎症反应中的作用。由于追踪特定抗原的低频T细胞的技术难题，目前还无法获得这一信息。T细胞受体转基因动物及其各自的抗原将被用来克服这一困难。这项技术将帮助我们描述被抗原特异性激活的T细胞的表型和功能，或者通过局部炎症部位的替代激活途径。我们的模型将是由查加西多诺瓦利什曼原虫（LCD）诱导的肉芽肿之一，其中T细胞对肉芽肿的形成至关重要。T细胞受体转基因小鼠的T细胞库仅包含两种不同的单特异性T细胞，将被表达仅被一种T细胞识别的表位的重组LCD感染。这些细胞的定位和激活阶段将被测量。将对这两种转基因T细胞群进行分类，并在过继转移研究中测试它们控制寄生虫负荷、形成肉芽肿和产生淋巴因子的能力。该实验将在野生型过继转移受体中重复，以检查正常人群中单特异性T细胞的功能。这些系统将用于研究免疫对特异性和非特异性T细胞的细胞因子和效应功能的影响。我们的应用程序有三个特定的目标。首先，我们将确定感染期间肉芽肿和免疫外周中抗原特异性和无关抗原限制性T细胞的比例。(目标1)。接下来，我们将研究寄生虫感染过程中这些特定种群的功能作用和特征（目标2）。最后，我们将使用疫苗来修饰T细胞，通过抗原特异性激活或通过肉芽肿中的其他激活途径，以便设计新的，精确靶向治疗寄生虫病中T细胞功能的疗法（目标3）。我们相信，本研究项目的成功完成将有助于进一步了解T细胞在肉芽肿性疾病中的作用，从而为控制利什曼病等肉芽肿性炎症性疾病的新治疗方法提供基础。

Early immunity to infectious agents generally involves a very well defined T cell response to a few immunodominant epitopes. However, the role of antigen specificity in T cell accumulation at chronic inflammatory sites is much less understood. The primary goal of this application is to understand the role of antigen and T cell receptor specificity in chronic granulomatous inflammatory reactions. This information is not presently available due to the technically challenging problem of tracing the low frequency T cells specific for a given antigen. T cell receptor transgenic animals and their respective antigens will be used to overcome this difficulty. This technology will help us to characterize the phenotype and function of T cells activated specifically by antigen or through alternative activation pathways within a localized inflammatory site. Our model will be one of granulomas induced by Leishmania chagasi donovani (LCD) where T cells are crucial for granuloma formation. T cell receptor transgenic mice with a T cell repertoire consisting only two different monospecific T cells will be infected with recombinant LCD expressing an epitope recognized by only one kind of the T cells. The localization and activation stages of these cells will be measured. The two transgenic T cell populations will be sorted and their capacity to control parasite load, form granulomas, and produce lymphokines will be tested in adoptive transfer studies. The experiments will be repeated in wild type adoptive transfer recipients to examine the function of the monospecific T cells within a normal population. These systems will be used to study the effects of immunization on cytokine and effector functions of specific and non-specific T cells. There are three Specific Aims for our application. First, we will determine the proportion of antigen-specific and unrelated antigen restricted T cells in granulomas and in the immune periphery during infection. (Aim 1). Next, we will study the functional role and characteristics of these defined populations throughout the parasitic infection (Aim 2). Finally, we will use vaccination to modify the T cells, activated specifically by antigen or through alternative activation pathways in the granulomas in order to design new, precisely targeted therapies for T cell functions in parasitic diseases (Aim 3). We believe that the successful completion of this research project will lead to an improved understanding of the role of T cells in granulomatous diseases and thus provide the foundation for new therapeutic methodologies for controlling granulomatous inflammatory diseases, such as leishmaniasis.