Development and function of invariant natural killer T cells producing T(h)2- and T(h)17-cytokines.
Development and function of invariant natural killer T cells producing T(h)2- and T(h)17-cytokines.
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DOI：
10.1371/journal.pbio.1001255
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发表时间：
2012-02
期刊：
影响因子：
9.8
通讯作者：
Taniguchi M
中科院分区：
文献类型：
--
作者：
Watarai H;Sekine-Kondo E;Shigeura T;Motomura Y;Yasuda T;Satoh R;Yoshida H;Kubo M;Kawamoto H;Koseki H;Taniguchi M
不变自然杀伤T细胞(NKT)的四个不同亚群在胸腺中分化，然后迁移到周围组织，在那里它们保持其表型和功能特征。在基于CD4和IL-17受体B(IL-17RB)表达的不变自然杀伤T细胞(INKT)中存在异质性，IL-17RB是IL-25的受体，IL-25是TH2免疫的关键因素。然而，这些iNKT细胞亚型的发育途径和确切功能仍不清楚。IL-17Rb+iNKT细胞存在于胸腺CD44+/−NK1.1−群体中，即使在没有IL-15的情况下也能正常发育，IL-15是IL-17Rb−iNKT细胞产生干扰素-γ成熟和动态平衡所必需的。提示iNKT细胞至少含有IL-17RB+和IL-17RB−亚群两种亚型。根据胸腺和外周血中CD4的表达情况，IL-17RB+iNKT亚型可进一步分为两个亚型。CD_4+IL-17RB+iNKT细胞以E4BP4依赖的方式刺激IL-25产生Th2(IL-13)、Th9(IL-9和IL-10)和Th17(IL-17A和IL-22)细胞因子，而CD_4−IL-17RB+iNKT细胞是视黄酸受体相关的γT+细胞亚群，在IL-23刺激下以E4BP4非依赖的方式产生Th17细胞因子。这些IL-17RB+iNKT细胞亚群在稳态期大量存在于肺组织中，参与了病毒诱导的呼吸道高反应性(AHR)的发病机制。在这项研究中，我们证明了IL-17RB+iNKT细胞亚群在胸腺中的发育不同于经典的iNKT细胞发育阶段，并在呼吸道疾病的发病机制中发挥重要作用。T细胞是参与细胞介导的获得性免疫的一组免疫细胞。T细胞的一个子集是先天不变的自然杀伤T细胞(INKT)，它识别靶细胞上的糖脂配体，而不是多肽。我们知道功能不同的iNKT细胞亚型参与了特定的病理过程，但对它们的发育、表型和功能还不清楚。在这里，我们确定了不同的小鼠iNKT细胞亚群之间的关系，为这些亚群确定了可靠的分子标记，并表明这些分子标记有助于它们的功能差异。我们确定了四个iNKT细胞亚群，它们通过不同的发育途径出现，并表现出不同的细胞因子谱。重要的是，我们发现这些亚群可以从胸腺(所有T细胞的器官)以及外围组织，如脾、肝、肺和淋巴结中分离出来。与一般的理解相反，iNKT细胞在离开胸腺并迁移到外周组织后成熟，我们得出结论，通过细胞因子受体IL-17RB和另一种细胞表面分子CD4的存在或不存在，可以在胸腺中区分不同的表型和功能的iNKT细胞亚群，然后这些亚群迁移到外周组织，在那里它们保持其表型和功能特征。在功能意义方面，我们表明那些导致呼吸道病毒高反应性的iNKT细胞亚群不同于那些导致过敏原诱导的呼吸道高反应性的细胞亚群，这将使研究人员能够将重点放在特定的亚群上，作为治疗干预的潜在靶点。
Four distinct subsets of invariant natural killer T (NKT) cells are shown to differentiate in the thymus, then migrate to peripheral tissues where they retain their phenotypic and functional characteristics. There is heterogeneity in invariant natural killer T (iNKT) cells based on the expression of CD4 and the IL-17 receptor B (IL-17RB), a receptor for IL-25 which is a key factor in TH2 immunity. However, the development pathway and precise function of these iNKT cell subtypes remain unknown. IL-17RB+ iNKT cells are present in the thymic CD44+/− NK1.1− population and develop normally even in the absence of IL-15, which is required for maturation and homeostasis of IL-17RB− iNKT cells producing IFN-γ. These results suggest that iNKT cells contain at least two subtypes, IL-17RB+ and IL-17RB− subsets. The IL-17RB+ iNKT subtypes can be further divided into two subtypes on the basis of CD4 expression both in the thymus and in the periphery. CD4+ IL-17RB+ iNKT cells produce TH2 (IL-13), TH9 (IL-9 and IL-10), and TH17 (IL-17A and IL-22) cytokines in response to IL-25 in an E4BP4-dependent fashion, whereas CD4− IL-17RB+ iNKT cells are a retinoic acid receptor-related orphan receptor (ROR)γt+ subset producing TH17 cytokines upon stimulation with IL-23 in an E4BP4-independent fashion. These IL-17RB+ iNKT cell subtypes are abundantly present in the lung in the steady state and mediate the pathogenesis in virus-induced airway hyperreactivity (AHR). In this study we demonstrated that the IL-17RB+ iNKT cell subsets develop distinct from classical iNKT cell developmental stages in the thymus and play important roles in the pathogenesis of airway diseases. T cells are a diverse group of immune cells involved in cell-mediated acquired immunity. One subset of T cells is the innate-like invariant natural killer T (iNKT) cells that recognize glycolipid ligands on target cells instead of peptides. We know that functionally distinct subtypes of iNKT cells are involved in specific pathologies, yet their development, phenotypes, and functions are not well understood. Here, we determine the relationship between various mouse iNKT cell subsets, identify reliable molecular markers for these subsets, and show that these contribute to their functional differences. We identify four iNKT cell subsets that we show arise via different developmental pathways and exhibit different cytokine profiles. Importantly, we show that these subsets can be isolated from the thymus (the organ of all T cells), as well as from peripheral tissues such as spleen, liver, lung, and lymph nodes. Contrary to the general understanding that iNKT cells mature after their exit from the thymus and their migration into peripheral tissues, we conclude that distinct phenotypic and functional iNKT cell subsets can be distinguished in the thymus by virtue of the presence or absence of the cytokine receptor IL-17RB and another cell surface molecule called CD4, and these subsets then migrate to peripheral tissues where they retain their phenotypic and functional characteristics. Regarding functional significance, we show that those iNKT cell subsets that lead to airway hyper-responsiveness to respiratory viruses are different to those that lead to allergen-induced airway hyperreactivity, which will enable researchers to focus on specific subsets as potential targets for therapeutic intervention.
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影响因子：
30.5
作者：
通讯作者：
--
影响因子：
5.8
作者：
Becnel, D;You, DH;Cormier, SA
通讯作者：
Cormier, SA
影响因子：
5.4
作者：
Kawamoto, H;Ohmura, K;Katsura, Y
通讯作者：
Katsura, Y
DOI：
10.1084/jem.20050456
发表时间：
2005-08-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Benlagha K;Wei DG;Veiga J;Teyton L;Bendelac A
通讯作者：
Bendelac A
DOI：
10.1084/jem.186.1.109
发表时间：
1997-07-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Exley M;Garcia J;Balk SP;Porcelli S
通讯作者：
Porcelli S