TRANSGENIC STUDIES OF TCR REPERTOIRE DIVESIFICATION

免疫系统的主要作用是区分自我 非自我。 抗原的特异性识别依赖于 淋巴细胞产生大量克隆受体的能力。 T细胞抗原受体（TCR）的可变区编码 通过分离的基因片段进行重排和连接 在T细胞发育过程中。 T细胞受体的主要来源 多样性存在于基因片段连接的位点， 添加连接核苷酸。 后一个过程似乎 与末端脱氧核苷酸转移酶（TdT）一致 活动，虽然TdT的贡献尚未正式 在活体中证明。 T细胞受体库的控制是必不可少的 自身免疫性疾病的预防。 虽然α β T细胞 在胸腺中进行选择; γ δ T细胞的位置 选择仍然是一个深入研究的课题。 在小鼠 胎儿期，γ δ T细胞前体表达的初始波 有限的连接多样性和选择的生殖细胞库。 成人 树突状表皮细胞（DEC）具有类似的生殖系TCR库 并且也表达很少的连接多样性。 在这项研究中，我们建议 为了创造在胎儿期高水平表达TdT的转基因小鼠， 生活 通过对TCR 1基因的γ δ TCR重排进行序列分析， 胎儿胸腺细胞，我们将测试不适当的TdT的影响 在体内产生N区多样性的活性。 通过 检查成人DEC细胞，我们将确定是否 在该T细胞亚群中发现的几乎单态性T细胞受体是 积极选择的结果，或者仅仅是因为它们来自 胎儿胸腺细胞同样不能表现出连接多样性。 这些研究不仅应该阐明控制 T细胞抗原受体库的多样化，但在 未来将使我们能够测试异常多样化的影响， γ β T细胞和其他细胞的发育 自身免疫性疾病的小鼠模型。

The primary role of the immune system is to discriminate between self and non-self. Specific recognition of antigen is dependent on the ability of lymphocytes to generate a wide array of clonal receptors. The variable regions of the T cell antigen receptors (TCR) are encoded by separated gene segments which undergo rearrangement and joining during T cell development. The major source of T cell receptor diversity resides at the site of gene segment joining and random addition of junctional nucleotides. This latter process appears coincidentally with terminal deoxynucleotidyl transferase (TdT) activity, although the contribution of TdT has not yet been formally proven in vivo. Control of the T cell receptor repertoire is essential to the prevention of autoimmune disease. Although alpha beta T cells are subjected to selection in the thymus; the site of gamma delta T cell selection is still a subject of intense investigation. During murine fetal life, initial waves of gamma delta T cell precursors express limited junctional diversity and a selected germline repertoire. Adult dendritic epidermal cells (DEC) bear a similar germline TCR repertoire and also express little junctional diversity. In this study, we propose to create transgenic mice which express TdT at high levels during fetal life. Through sequence analysis of gamma delta TCR rearrangements in fetal thymocytes, we will test the influence of inappropriate TdT activity on the generation of N region diversity in vivo. Through examination of adult DEC cells, we will determine whether or not the virtually monomorphic T cell receptors found in this T cell subset is the result of positive selection, or simply due to their derivation from fetal thymocytes which similarly fail to exhibit junctional diversity. These studies should not only shed light on the mechanisms which control diversification of the T cell antigen receptor repertoire, but in the future will allow us to test the effect of abnormal diversification of the repertoire on the development of gamma beta T cells and in other mouse models of autoimmune disease.