Structural Requirements of glycolipid/CD1d Recognition by NKT Cells

摘要 自然杀伤T(INKT)细胞代表一种淋巴细胞群体，它已经进化到能够识别 CD1d提呈的糖脂抗原。一旦识别糖脂，iNKT细胞就会在 小时，让人联想到与生俱来的功能，而不是适应性功能。这些细胞被牵连到 调节与一系列疾病相关的免疫反应，包括自身免疫， 传染病和癌症。INKT细胞表达高度受限的TCR谱系，原因是 不变的V？14-J？18序列的使用和V？8.2、V？7和V？2的优先使用 基因片段。TCR结构的最大多样性仅限于TCR的CDR3区域 链条。我们最近的研究结果表明，TCR链的作用是调节总的亲和力 TCR用于抗原/CD1d复合体，而不是促进不同抗原的识别。 这项资助的总体目标是更全面地了解iNKT细胞的形成 以及高亲和力的iNKT细胞来源的TCR是否可以用作战斗中的功能工具 抗癌。 所提出的实验将检验：1)iNKT细胞谱的V？偏置是否 由每个V？结合CD1d的能力决定，2)iNKT细胞前体是否高表达 亲和力TCR在发育过程中是负选择的，以及3)高亲和力iNKT细胞- 衍生的TCR可用于过继细胞转移治疗抗癌。 更好地理解iNKT TCR对糖脂的识别以及它可能如何影响iNKT 细胞功能将允许对iNKT细胞配体进行合理优化，并将为 微调iNKT细胞功能。

Summary Natural Killer T (iNKT) cells represent a lymphocyte population that has evolved to recognize glycolipid antigens presented by CD1d. Upon recognition of glycolipids, iNKT cells respond within hours, reminiscent of innate rather than adaptive functions. These cells have been implicated in the regulation of immune responses associated with a broad range of diseases, including autoimmunity, infectious diseases and cancer. iNKT cells express a highly restricted TCR repertoire, due to the usage of an invariant V¿14-J¿18 sequence and the preferential usage of the V¿8.2, V¿7 and V¿2 gene segments. The most diversity of the TCR structure is limited to the CDR3 region of the TCR¿ chain. Our recent results suggest that the role of the TCR¿ chain is to modulate the overall affinity of the TCR for the antigen/CD1d complex rather than to facilitate recognition of different antigens. The overall goal of this grant is to understand more fully the formation of the iNKT cell repertoire and whether high affinity iNKT-cell-derived TCRs can be used as functional tools in the fight against cancer. The experiments proposed will examine: 1) whether the V¿ bias of the iNKT cell repertoire is dictated by the ability of each V¿ to bind CD1d, 2) whether iNKT cell precursors that express high affinity TCRs are negatively selected during development and 3) whether high affinity iNKT cell- derived TCRs can be used for adoptive cell transfer therapy against cancer. A better understanding of glycolipid recognition by the iNKT TCR and how it might affect iNKT cell functions will allow for the rational optimization of iNKT cell ligands and will define guidelines for fine tuning iNKT cell function.