Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
PLoS One. 2010 Dec 17;5(12):e14374. doi: 10.1371/journal.pone.0014374.
CD1d-restricted natural killer T cells with invariant T cell receptor α chains (iNKT cells) are a unique lymphocyte subset that responds to recognition of specific lipid and glycolipid antigens. They are conserved between mice and humans and exert various immunoregulatory functions through their rapid secretion of a variety of cytokines and secondary activation of dendritic cells, B cells and NK cells. In the current study, we analyzed the range of functional activation states of human iNKT cells using a library of novel analogs of α-galactosylceramide (αGalCer), the prototypical iNKT cell antigen. Measurement of cytokines secreted by human iNKT cell clones over a wide range of glycolipid concentrations revealed that iNKT cell ligands could be classified into functional groups, correlating with weak versus strong agonistic activity. The findings established a hierarchy for induction of different cytokines, with thresholds for secretion being consistently lowest for IL-13, higher for interferon-γ (IFNγ), and even higher for IL-4. These findings suggested that human iNKT cells can be intrinsically polarized to selective production of IL-13 by maintaining a low level of activation using weak agonists, whereas selective polarization to IL-4 production cannot be achieved through modulating the strength of the activating ligand. In addition, using a newly designed in vitro system to assess the ability of human iNKT cells to transactivate NK cells, we found that robust secondary induction of interferon-γ secretion by NK cells was associated with strong but not weak agonist ligands of iNKT cells. These results indicate that polarization of human iNKT cell responses to Th2-like or anti-inflammatory effects may best be achieved through selective induction of IL-13 and suggest potential discrepancies with findings from mouse models that may be important in designing iNKT cell-based therapies in humans.
CD1d 限制性天然杀伤 T 细胞（iNKT 细胞）具有不变的 T 细胞受体 α 链，是一种独特的淋巴细胞亚群，能够识别特定的脂质和糖脂抗原。它们在小鼠和人类之间是保守的，通过快速分泌各种细胞因子和二级激活树突状细胞、B 细胞和 NK 细胞来发挥各种免疫调节功能。在本研究中，我们使用一系列新型半乳糖基神经酰胺（αGalCer）类似物分析了人类 iNKT 细胞的功能激活状态范围，αGalCer 是典型的 iNKT 细胞抗原。测量广泛浓度范围内的人 iNKT 细胞克隆分泌的细胞因子表明，iNKT 细胞配体可以分为功能组，与弱激动剂和强激动剂活性相关。这些发现确定了诱导不同细胞因子的层次，细胞因子分泌的阈值对于 IL-13 始终最低，对于 IFNγ（IFNγ）较高，对于 IL-4 甚至更高。这些发现表明，通过使用弱激动剂维持低水平的激活，人类 iNKT 细胞可以固有地偏向于选择性产生 IL-13，而通过调节激活配体的强度，无法实现选择性偏向于 IL-4 的产生。此外，使用新设计的体外系统评估人类 iNKT 细胞激活 NK 细胞的能力，我们发现 NK 细胞干扰素-γ分泌的强烈二次诱导与 iNKT 细胞的强但不是弱激动剂配体相关。这些结果表明，人类 iNKT 细胞反应向 Th2 样或抗炎作用的极化可能通过选择性诱导 IL-13 来实现，并表明与小鼠模型的发现可能存在差异，这在设计人类基于 iNKT 细胞的治疗方法时可能很重要。
