CD1d2-Selected iNKT Cells

描述（由申请人提供）：CD 1d分子将脂质和糖脂抗原呈递给具有重要免疫调节特性的独特T细胞亚群，即NKT细胞。小鼠中的大多数NKT细胞使用不变的TCR a链，具有Va 14-Ja 18重排，与有限数量的V ²链配对。另一群CD 1d反应性T细胞也存在，表达更多样化的TCR库，但其特征仍然很差。虽然小鼠基因组包含两个编码CD 1d蛋白的基因，但其中只有一个CD 1d 1对NKT细胞的生物学很重要。我们的初步结果证实，在CD 1d 2分子上选择的一些iNKT细胞实际上存在于CD 1d 1-/-小鼠的组织中。CD 1d 1和CD 1d 2基因产物相差17个氨基酸，其中16个位于蛋白质的a1和a2结构域，因此可能影响抗原呈递和/或识别。这些结果提高了CD 1d 2分子可能在NKT细胞生物学中发挥独特作用的可能性。我们建议进一步表征CD 1d 2选择的iNKT细胞，并测试这些细胞是否在野生型环境中发育。 公共卫生相关性：自然杀伤T细胞（NKT细胞）在调节各种免疫反应中发挥重要作用。近年来，关于这些细胞如何发育、识别其抗原并影响免疫反应，已经取得了几项重大进展。然而，我们发现一些iNKT细胞即使在没有CD 1d 1分子表达的情况下也会继续发育，这挑战了目前关于这些细胞发育的教条。拟议的研究旨在进一步表征在CD 1d 1缺陷小鼠中发育的iNKT细胞的表型和功能。了解iNKT细胞发育和稳态对于了解这些细胞的功能至关重要，以便它们可以用于治疗用途以改善人类健康。

DESCRIPTION (provided by applicant): CD1d molecules present lipid and glycolipid antigens to a unique subset of T cells with important immunoregulatory properties, the NKT cells. Most of the NKT cells in mice use an invariant TCR a-chain, with Va14-Ja18 rearrangement, paired with a limited number of V¿ chains. Another population of CD1d-reactive T cells also exists that expresses a more diverse TCR repertoire, but it remains poorly characterized. While the mouse genome contains two genes that encode for CD1d proteins, only one of them, CD1d1, appear important to the biology of NKT cells. Our preliminary results establish that some iNKT cells selected on CD1d2 molecules are in fact present in the tissues of CD1d1-/- mice. CD1d1 and CD1d2 gene products differ by 17 amino acids, with 16 of them located in the a1 and a2 domains of the protein that could therefore influence antigen presentation and/or recognition. These results raise the possibility that CD1d2 molecules might play a unique role in NKT cell biology. We propose to further characterize CD1d2-selected iNKT cells and to test whether these cells develop in a wildtype environment. PUBLIC HEALTH RELEVANCE: Natural Killer T cells (NKT cells) play an important role in regulating a variety of immune responses. Several major advances have been made in the recent years regarding how these cells develop, recognize their antigens and influence immune responses. Yet, our finding that some iNKT cells continue to develop even in absence of CD1d1 molecule expression challenges the current dogma regarding the development of these cells. The proposed studies aim at further characterizing phenotypically and functionally the iNKT cells that develop in CD1d1-deficient mice. An understanding of iNKT cell development and homeostasis is of fundamental importance to understand the function of these cells so that they can be exploited for therapeutic usage to improve human health.