Invariant natural killer T cells act as an extravascular cytotoxic barrier for joint-invading Lyme Borrelia
Woo‐Yong LeeMaría‐Jesús SanzConnie H. Y. WongPierre‐Olivier HardyAydan Salman‐DilgimenTara J. MoriartyGeorge ChaconasAdriana MarquesRoman KrawetzChristopher H. ModyPaul Kubes
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Significance Invariant natural killer T cells (iNKT) have been found primarily patrolling inside blood vessels in the liver, where they respond to bacterial glycolipids presented by CD1d on liver macrophages. We show joint iNKT cells are localized outside of blood vessels and respond directly to the joint-homing pathogen, Borrelia burgdorferi , which causes Lyme borreliosis using multichannel spinning-disk intravital microscopy. These iNKT cells interacted with B. burgdorferi at the vessel wall and disrupted its dissemination attempts into joints. Successful penetrance of B. burgdorferi out of the vasculature and into the joint tissue was met by a lethal attack by extravascular iNKT cells through a granzyme-dependent pathway. These results suggest a critical extravascular iNKT cell immune surveillance in joints that functions as a cytotoxic barrier.Keywords:
Homing (biology)
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Bystander effect
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KRN7000, an anticancer drug candidate developed by Kirin Brewery Co. in 1995, is an α-galactosyl ceramide. It is a ligand making a complex with CD1d protein, and it stimulates invariant natural killer T (NKT) cells, which are one of the lineages of immunocytes. NKT cells activated by recognition of the CD1d/KRN7000 complex with its invariant T-cell receptor (TCR) can induce both protective and regulatory immune responses. To determine the recognition and activation mechanisms of NKT cells and to develop drug candidates more effective than KRN7000, a large number of analogs of KRN7000 have been synthesized. Some of them show potent bioactivities and have the potential of being utilized as therapeutic agents. In this review, structure-activity relationship studies of novel glycolipids which stimulate NKT cells efficiently are summarized.
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Natural killer T (NKT) cells are a subset of regulatory T lymphocytes that recognize glycolipid antigens presented by the major histocompatibility complex class I-related glycoprotein CD1d. NKT cells have been implicated in regulating the progression of Type 1 diabetes (T1D) in human patients and in an animal model for T1D. In addition, glycolipid agonists of NKT cells have been successful in preventing diabetes in mice, raising enthusiasm for the development of NKT cell-based therapies for T1D.
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Abstract Natural killer T cells (NKT) are a unique subset of lymphocytes that bridge the gap between innate and adaptive immunity. Unlike conventional T cells that recognize MHC-presented antigen, NKT cells recognize lipid antigen presented by CD1d, and two types of NKT cells recognize different sets of antigens. Type I NKT cells have been extensively studied by using CD1d tetramers or dimers loaded with α-galactosylceramide (α-GalCer), a type I specific lipid antigen. In contrast, studying type II NKT cells has remained elusive because it has been difficult in many labs to make CD1d tetramers to identify this subset with the best characterized antigen known to stimulate specifically a large fraction of type II NKT cells, sulfatide. The methodology used to load α-GalCer onto CD1d has failed to provide reproducible outcomes when used to load sulfatide. In this study, we have developed sulfatide loaded CD1d dimers that can accurately identify type II NKT cells. Using the knowledge of the endogenous lipid loading conditions onto CD1d, we developed a method to load lipid antigens onto CD1d dimers for flow cytometry. By using both saposin C, a chaperone protein necessary for lipid loading, and acidic conditions, as found in the endosome in which lipid loading onto CD1d occurs, we can reliably create sulfatide-loaded CD1d dimers to identify type II NKT cells. Sulfatide-loaded CD1d dimers specifically identify type II NKT cells in both WT and type I NKT deficient mice, but do not detect cells in CD1d -/- mice that lack both types of NKT cells, as expected. The specificity of the binding of dimers through TCRβ is also confirmed by TCRβ blockade. Consistent with previous findings in the liver, the sulfatide-reactive type II NKT cell population encompasses about 2% of all lymphocytes, and is completely distinct from its type I counterpart, which represents approximately 10% of liver lymphocytes; no double positive cells were detected. In addition, although the predominant Vβ usage for both subsets is Vβ8.1/8.2, the type II cells include cells expressing Vβ9 and 13, but not Vβ 2 and 7, in contrast to type I NKT cells. Additionally, we observed a sulfatide reactive NKT population in human PBMCs that is Vα24-Vβ11- and comparable in numbers to type I NKT cells, which are Vα24+Vβ11+. All these data suggest that the method we developed can create sulfatide-loaded CD1d dimers in a highly reproducible manner that can identify type II NKT cells. This method to load glycolipids antigens onto recombinant CD1d molecules has enabled us to not only identify a type II NKT cell subset based on previous knowledge of these cells, but also expand on that by potentially identifying other markers. Ultimately, this method of loading previously problematic lipids onto CD1d dimers may allow for their use to identify many more subsets of NKT cells across multiple models. Citation Format: Stanley Parish, Liat Izhak, Zheng Xia, Motoshi Suzuli, Masaki Terabe, Jay A. Berzofsky. Identification of sulfatide reactive type II NKT cells using CD1d dimers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1262. doi:10.1158/1538-7445.AM2013-1262
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It has been established that α-galactosylceramide (α-GalCer), a glycolipid, is recognized by natural killer T (NKT) cells together with the monomorphic MHC-like antigen, CD1d, in mice and humans. In this study, we examined how NKT cells are modulated by in vivo administration of α-GalCer in mice. When 2 μg (or more)/mouse of α-GalCer was injected i.p., the majority of NKT cells disappeared in the liver and spleen, possibly undergoing apoptosis, on day 1. At this time, NKT cytotoxicity seen in liver lymphocytes also disappeared. In parallel with this numerical and functional change of NKT cells, there was always concomitant hepatocyte damage, as shown by histology and elevated levels of transaminases. Subsequently, the number and function of NKT cells continued to increase from day 3 to day 7. The response seen in hepatic (and splenic) NKT cells did not occur in thymic NKT cells. All these phenomena induced in the liver did not appear in NKT-deficient mice such as β2-microglobulin–/– and CD1d–/– mice. These results shed further light on the in vivo interaction between NKT cells and α-GalCer in mice.
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Abstract Natural killer T cells (NKT) are a unique subset of lymphocytes that bridge the gap between innate and adaptive immunity by recognizing lipid antigen presented by CD1d. While type I NKT cells have been extensively studied by using CD1d multimers loaded with α-galactosylceramide (α-GalCer), a type I specific antigen, studying type II NKT cells has lagged behind, since loading sulfatide, a type II-specific lipid antigen, to the tetramer has been difficult to accomplish reliably. In this study, we have developed sulfatide loaded CD1d dimers that accurately identify type II NKT cells by flow cytometry. Using saposin C, a lipid loading chaperone protein, and acidic conditions, as found in the natural loading environment, we could create sulfatide-loaded CD1d dimers to identify this subset. Sulfatide-loaded CD1d dimers specifically identified type II NKT cells in both WT and type I NKT deficient mice, and were not observed in NKT cell-deficient CD1d-/- mice. The specificity of the binding through TCRβ was confirmed by TCRβ blockade. Consistent with previous findings, in the liver, the sulfatide-reactive type II NKT cells were a distinct population that encompasses about 2% of liver lymphocytes. These data suggest that the method we developed can create sulfatide-loaded CD1d dimers to identify type II NKT cells, and has enabled us to identify other markers of this subset. This method can be used to load other lipids onto CD1d to identify other NKT subsets across multiple models.
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