INHERITED CONTROL MECHANISMS IN IG GENE EXPRESSION

这项研究的长期目标是更好地理解MHC类 II-限制性抗原提呈。IIa/β类杂二聚体 在细胞内与第三个多肽链相结合，不变量 链，这会影响第二类成熟。一项重大贡献，由 在过去的支持期间，这个实验室是一部小说的代名词 携带不变链基因定点突变的小鼠品系 以及对其显著表型的描述。建议进行的实验 这一应用旨在进一步分析不变链的能力 影响MHC II类分子在表面的结构 在完好的动物体内有不同的抗原提呈细胞。我们计划 比较产生的II类分子的不变链依赖性 不同MHC背景和评估IL_4/内毒素的可能作用(S) 对II类成熟的刺激作用。我们还将研究生物合成 树突状细胞表达的II类分子的成熟， 激活的巨噬细胞和胸腺基质细胞。第二个目标是 进一步分析MHC相关II链对CD4+T细胞的贡献 细胞成熟。我们计划测试剩下的少数几个 II小鼠体内存在的CD4T细胞可能部分地代表了一种中间体 选定的CD_4亚群。我们将检查他们的V/Beta曲目，以及 确定这些细胞是否被触发增殖和/或产生 淋巴因子对TCR交联物的反应。此外，胸腺器官 培养物将用于研究有缺陷的CD4+T细胞的成熟。我们 将寻找按肽进行正选择的证据，并评估 新出现的CD4+T细胞克隆的V/β谱系。最后，一个主要目标 是考察S在结构上扮演的潜在分歧角色 不同的Ii31和41蛋白作为替代的结果出现 信使核糖核酸剪接我们计划培育出转基因小鼠品系 独家表达p31或p41形式的不变链蛋白，该蛋白 在体内也显示了适当的组织特异性表达模式。 这些新的小鼠品系将被用来分析 不变链P31和/或P41单独影响第二类生物化学， APC活性和T细胞选择。总的来说，这些 实验有望提供对功能的进一步洞察 MHC-II类相关II链在免疫中的作用(S) 监管。

The long-term goal of this research is to better understand MHC class II-restricted antigen presentation. Class II a/beta heterodimers associate intracellularly with a third polypeptide chain, the invariant chain, that affects class II maturation. A significant contribution by this lab during the past period of support was the generation of a novel mouse strain carrying a targeted mutation at the invariant chain locus and the description of its striking phenotype. Experiments proposed in this application aim to further analyze the ability of invariant chain to affect the structure of MHC class II molecules on the surface of diverse antigen-presenting cells in the intact animal. We plan to compare the invariant chain dependency of class II molecules produced in different MHC backgrounds and to evaluate possible effect(s) of IL4/LPS stimulation on class II maturation. We will also examine biosynthesis and maturation of class II molecules expressed by dendritic cells, activated macrophages, and thymic stromal cells. A second goal is to further analyze the contribution of MHC-associated Ii chain to CD4+ T cell maturation. We plan to test the possibility that the few remaining CD4 T cells present in Ii mice may represent an intermediate, partially selected CD4 subset. We will examine their V/beta repertoire, and determine if these cells are triggered to proliferate and/or produce lymphokines in response to TCR crosslinking. Additionally, thymic organ cultures will be used to study defective CD4+ T cell maturation. We will seek evidence for positive selection by peptide and evaluate the V/beta repertoire of emerging CD4+ T cell clones. Finally, a major goal is to examine potentially divergent role(s) played by structurally distinct Ii31 and 41 proteins that arise as the result of alternative mRNA splicing. We plan to generate transgenic mouse strains that exclusively express the p31 or p41 form of invariant chain protein that also show an appropriate tissue-specific pattern of expression in vivo. These novel mouse strains will be used to analyze the capacity of invariant chain p31 and/or p41 alone to affect class II biochemistry, APC activity, and T cell selection in these strains. Overall, these experiments will hopefully provide further insight into functional role(s) played by the MHC class II-associated Ii chain in immune regulation.