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

不变的自然杀伤T（iNKT）细胞代表执行专门功能的T细胞亚群。iNKT细胞存在于胸腺中，并来源于双阳性胸腺细胞。募集到iNKT途径中的细胞表达一组高度限制的α/β TCR，这使得名称不变。这些TCR能够识别非肽组分，如糖脂，其在CD 1d（一种与MHC I类相关的多肽）的背景下呈递给iNKT细胞。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。与传统的通过发育中间体定义iNKT亚群的假设不同，出现了一个新的概念，称为谱系多样性模型。这种新的模型在文献中获得了快速的接受，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物的表达足以清楚地定义三个具有不同细胞因子表达谱的iNKT亚群。实际上，iNKT细胞类似于效应CD 4 T细胞，并且根据谱系多样性模型定义的三个iNKT亚群主要产生IFN-γ或IL-4或IL-17，因此它们分别被命名为iNKT 1、iNKT 2和iNKT 17细胞，类似于已确立的T辅助细胞范例。然而，主要由于其新奇，iNKT 1/2/17概念在涉及外周iNKT细胞时缺乏广泛的实验支持。iNKT细胞可以在几乎所有外周淋巴以及非淋巴器官如肝、肺和肠中发现，并且可以想象器官特异性微环境将功能特性印记到地方性iNKT群体上。因此，我们计划通过从几个器官中分离的外周iNKT亚群的综合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。这将通过外周iNKT亚群的迁移和分化潜力的研究来补充。它们的功能方面将在结肠炎和哮喘的几种小鼠模型中进一步阐明。它还旨在关注不同基因缺陷对iNKT细胞功能和/或分化的影响。在我们早期的工作过程中，我们已经确定了几个候选基因，并期望这里提出的实验将揭示影响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.