Phenotypical and functional characterization of murine iNKT1, 2, and 17 cells.

不变自然杀伤T细胞(INKT)代表T细胞亚群执行特殊功能。INKT细胞存在于胸腺中，来源于双阳性胸腺细胞。被招募到iNKT途径中的细胞表达一组高度受限的α/βTCR，由此产生了不变量这个名称。这些TCR能够识别在CD1d背景下呈递给iNKT细胞的非肽成分，如糖脂，CD1d是一种与MHC I类相关的多肽。最近，我们对iNKT细胞分化和功能的理解发生了根本性的重新定位。与经典的用发育中间体定义iNKT亚集的假说不同，出现了一个新的概念，称为谱系多样性模型。这一新模型在文献中迅速被接受，因为它能够将iNKT子集的简单定义与功能方面相关联。因此，几个关键转录因子或表面标记的表达足以清楚地定义具有不同细胞因子表达谱的三个iNKT亚群。事实上，iNKT细胞类似于效应CD4T细胞，根据谱系多样性模型定义的三个iNKT亚群主要产生干扰素-γ、IL-4或IL-17，因此它们分别被命名为iNKT1、iNKT2和iNKT17细胞，类似于公认的T辅助细胞范例。然而，主要由于其新颖性，当提到外周的iNKT细胞时，iNKT1/2/17概念缺乏广泛的实验支持。INKT细胞几乎存在于所有的外周淋巴组织和非淋巴组织器官，如肝、肺和肠，可以想象，器官特异性的微环境在地方性iNKT群体中留下了功能的印记。因此，我们计划通过对分离自几个器官的外周iNKT亚群进行全面的比较研究来破译这些特征。为了捕捉差异，我们将进行比较转录组分析。这将通过研究外周iNKT亚群的迁移和分化潜力来补充。它们的功能方面将在几种结肠炎和哮喘的小鼠模型中进一步阐明。它还打算集中在明显的基因缺陷对iNKT细胞的功能和/或分化的后果。在我们早期的工作中，我们已经确定了几个候选基因，并预计这里提出的实验将揭开影响iNKT细胞生物学的其他基因。

Invariant natural killer T (iNKT) cells represent a subpopulation of T cells performing specialized functions. iNKT cells come into existence in thymus and are derived from double positive thymocytes. Cells recruited into the iNKT pathway express a highly restricted set of alpha/beta TCR coining the name invariant. These TCR are capable to recognize non-peptide components such as glycolipids that are presented to iNKT cells in the context of CD1d, a polypeptide related to MHC class I.Recently, there was a fundamental reorientation in our understanding of iNKT cell differentiation and function. In contrast to the classical hypothesis defining iNKT subsets by developmental intermediates, a new concept emerged called lineage diversity model. This new model gained quick acceptance in the literature due to its capability to correlate a simple definition of iNKT subsets with functional aspects. Thus, expression of a few key transcription factors or surface markers suffices to clearly define three iNKT subpopulations possessing distinct cytokine expression profiles. Indeed, iNKT cells resemble effector CD4 T cells and the three iNKT subsets defined according to the lineage diversity model predominantly produce either IFN-gamma, or IL-4 or IL-17 wherefore they are named iNKT1, iNKT2, and iNKT17 cells, respectively, in analogy to the well-established T helper cell paradigm. Nevertheless, mainly due to its novelty, the iNKT1/2/17-concept lacks a broad experimental support when referring to iNKT cells of the periphery. iNKT cells can be found in virtually all peripheral lymphoid as well as non-lymphoid organs such as liver, lung and intestine and it is conceivable that organ-specific micro-milieus imprint functional peculiarities onto the endemic iNKT populations. Therefore, we plan to decipher such features by a comprehensive comparative study of peripheral iNKT subpopulations isolated from several organs. To capture differences, we will perform comparative transcriptome analyses. This will be complemented by studies of the migratory and differentiation potential of peripheral iNKT subsets. Their functional aspects will be further elucidated in several mouse models of colitis and asthma. It is also intended to focus on the consequences of distinct gene deficiencies on the function and/or differentiation of iNKT cells. In the course of our earlier work, we already identified several candidate genes and would expect that the experiments proposed here will unravel additional genes that influence iNKT cell biology.