Organic killer T (NKT) cells certainly are a unique subset of T lymphocytes with the expression of T cell receptor (TCR) and NK cell lineage receptors. a blood-brain barrier (BBB) and the lack of lymphatic drainage. Researchers focused mainly on neurons or glial cells when investigating the underlying molecular mechanism of neurological disorders (Price et al., 1987; Almad and Maragakis, 2012). However, mounting evidence highlights the importance of neuroinflammation in neurological diseases (Schwartz and Deczkowska, 2016; Fung et al., 2017; Skaper et al., 2018). In addition, the recently discovered glymphatic system and meningeal lymphatics uncovers a way for peripheral immune cells to enter the brain and communicate with resident cells (Da Mesquita et al., 2018; Sun et al., 2018). Thus, the function of peripheral immune cells in neurological diseases should motivate and be investigated by more researchers. Natural killer T cells are unique CD1d-restricted T lymphocytes that function as a bridge between innate and adaptive immunity. Based on their TCR usage and lipid antigen specificity, NKT cells have been divided into two subpopulations, type I and type II. Both of these subpopulations recognize lipids antigens presented by CD1d (Bendelac et al., 2007; Godfrey et al., 2010; Nishioka et al., 2018). NKT cells account for a small percentage of lymphocytes, but have profound immunomodulatory roles in a variety of diseases, as these cells show both innate, and adaptive immunological features (Taniguchi et al., 2003; Brennan et al., 2013). Given the abundant existence of glycosphingolipids in the brain (Hirabayashi, 2012), we wondered whether and how NKT cells functioned in neurological diseases. In this review, we described NKT cell properties, summarized current reports on the functions of NKT cells in neurological disorders, including ischemic stroke, brain tumor, multiple sclerosis (MS), neurodegenerative disease and other neurological disorders, and discussed immunotherapeutic potential of these cells and the goals of future studies. NKT Cell Classification and Effector Function Lanatoside C Natural killer T cells are a specialized subset of T cells that express TCR and NK cell lineage markers, such as NK1.1, NKG2D, and Ly49A. There are two broad categories of NKT cells, type I, and type II. Type I NKT cells, known as invariant NKT cells (iNKT cells) typically express an invariant V14-J18 TCR chain and a limited number of non-invariant TCR Rabbit Polyclonal to GAS1 chains that recognize -galactosylceramide (-GalCer), a glycosphingolipid isolated from the marine sponge, presented by CD1d. In addition, an increasing number of endogenous antigens, such as isoglobotrihexosylceramide (iGb3) and disialoganglioside (GD3), have also been discovered. Conversely, type II NKT cells use diverse TCR and stores which are reactive to even more wide antigens, such as glycolipids, phospholipids, and hydrophobic antigens (Bendelac et al., 2007; Godfrey et al., 2010; Nishioka et al., 2018; Figure 1A). Genetic tools have been generated to study NKT cell development and function based on the TCR composition of type I and type II NKT cells. V14J18 transgenic mice and J18?/? mice were used to enrich and delete type I NKT cells, respectively (Bendelac et al., 1996; Cui Lanatoside C et al., 1997). In contrast to the J18?/? mouse, CD1d?/? mice lack both type I and type II NKT cells, as CD1d is essential for the positive selection of both subsets in the thymus (Chen et al., 1997). Unlike type I NKT cells, whose development and function have been well investigated, the functional role of type II NKT cells is less clear due to the lack of universal and specific staining antibodies, although these cells are more prevalent in humans than type I NKT cells are (Dhodapkar and Kumar, 2017). Lanatoside C Open in a separate window FIGURE 1 NKT cell classification. (A) Properties of Type I (iNKT) and type II NKT cell (vNKT) subpopulations based on the composition of TCR. (B) Major subsets of iNKT cells. Transcription factors and cytokines associated with each subset are shown. T-bet, T-box transcription factor; GATA3, GATA-binding protein 3; RORt, retinoic acid receptor-related orphan receptor-t; PLZF, promyelocytic leukemia zinc finger protein; Bcl6, B-Cell Lymphoma 6; IFN, interferon-; IL-2, Interleukin 2. Natural killer T cells can quickly secrete large quantities of cytokines, such as interferon- (IFN-), IL-17, IL-4, and IL-10, which are important for the initiation and regulation of various immune responses (Brennan et al., 2013). Researchers have recently described a new classification system according to the cytokines and transcription factors expressed by type I NKT cells, namely, Th1-like iNKT cell (iNKT1), Th2-like iNKT cell (iNKT2), Th17-like iNKT cell (iNKT17), and Tfh-like iNKT cell (iNKTfh) (Chang et al., 2011; Engel et al., 2016; Figure 1B). The effector function of NKT cells is determined by the differentiation potential of these effector.