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Structural Requirements of glycolipid/CD1d Recognition by NKT Cells

NKT 细胞识别糖脂/CD1d 的结构要求

基本信息

批准号：
8113697
负责人：
Laurent Gapin
金额：
$ 6.71万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-20 至 2011-04-30
项目状态：
已结题

项目摘要

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.

概括自然杀伤 T (iNKT) 细胞代表淋巴细胞群，已进化到能够识别 CD1d 呈递的糖脂抗原。在识别糖脂后，iNKT 细胞会在小时，让人想起与生俱来的功能，而不是适应性功能。这些细胞与调节与多种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 库，这是由于使用不变的 V¿14-J¿18 序列以及优先使用 V¿8.2、V¿7 和 V¿2 基因片段。 TCR 结构的多样性仅限于 TCR 的 CDR3 区域¿ 链。我们最近的结果表明，TCR¿ 链的作用是调节抗原/CD1d复合物的TCR，而不是促进不同抗原的识别。本次资助的总体目标是更全面地了解 iNKT 细胞的形成库以及高亲和力 iNKT 细胞衍生的 TCR 是否可以用作战斗中的功能工具对抗癌症。提议的实验将检查：1) iNKT 细胞库的 V¿ 偏差是否是由每个 V¿ 结合 CD1d 的能力决定，2) 是否表达高表达的 iNKT 细胞前体亲和力 TCR 在发育过程中被负选择，3) 是否高亲和力 iNKT 细胞- 衍生的 TCR 可用于针对癌症的过继细胞转移疗法。更好地了解 iNKT TCR 的糖脂识别及其对 iNKT 的影响细胞功能将允许 iNKT 细胞配体的合理优化，并将定义指导方针微调 iNKT 细胞功能。