Generation of TRAJ18-Deficient Mice Using TALNS

描述（由申请人提供）：自然杀伤T（NKT）细胞参与调节与多种疾病相关的免疫应答，包括自身免疫、过敏、感染性疾病和癌症。NKT细胞在疾病中的作用的研究依赖于两种相似但不等同的小鼠模型，这两种模型都具有NKT细胞缺陷。在一个模型中，CD 1d编码基因已被删除，从而防止任何CD 1d反应性T细胞的发展，包括但不限于NKT细胞。另一种模型直接靶向TRAJ 18基因片段，其与TRAV 11基因组合绝对需要形成具有适当抗原特异性的NKT T细胞受体（TCR）。TRAJ 18缺陷小鼠（J 18-/-）自1997年生产以来，已在700多篇出版物中引用，突出了这种小鼠模型的重要性。使用高通量测序，我们最近观察到，除了NKT细胞缺乏外，J <$18-/-小鼠的常规T细胞库显著减少。因此，NKT细胞领域迫切需要一种新的小鼠模型，以允许不间断地研究NKT细胞生物学。我们建议产生一种新的小鼠品系，其中J 18基因片段将被特异性和独特地修饰，以破坏NKT细胞的产生，而不显著改变传统的T细胞区室使用转录激活因子样效应核酸酶（TALEN）。

DESCRIPTION (provided by applicant): Natural Killer T (NKT) cells have been implicated in the regulation of immune responses associated with a broad range of diseases, including autoimmunity, allergy, infectious disease and cancer. The study of the role of NKT cells in disease relies upon two similar but not equivalent mouse models, both of which have NKT cell deficiencies. In one model, the CD1d-encoding genes have been deleted, thereby preventing the development of any CD1d-reactive T cells, including, but not limited to, NKT cells. Another model directly targeted the TRAJ18 gene segment, which in combination with TRAV11 gene is absolutely required to form the NKT T cell receptor (TCR) with the appropriate antigenic specificity. Highlighting the importance of such mouse model, TRAJ18-deificient mice (J¿18-/-) have been cited in over 700 publications since their production in 1997. Using high-throughput sequencing, we recently made the observation that the J¿18-/- mouse has a significantly reduced conventional T cell repertoire in addition to a deficiency in NKT cells. As such, the NKT cell field urgently requires a new mouse model to permit the uninterrupted study of NKT cell biology. We propose to generate a new mouse strain in which the J¿18 gene segment will be specifically and uniquely modified to disrupt the generation of NKT cells without significantly altering the conventional T cell compartment using transcription activator-like effector nucleases (TALENs).