Glycolipid antigen induces long-term natural killer T cell anergy in mice
Vrajesh V. Parekh, … , Sebastian Joyce, Luc Van Kaer
Vrajesh V. Parekh, … , Sebastian Joyce, Luc Van Kaer
Published September 1, 2005
Citation Information: J Clin Invest. 2005;115(9):2572-2583. https://doi.org/10.1172/JCI24762.
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Research Article Immunology

Glycolipid antigen induces long-term natural killer T cell anergy in mice

Abstract

Natural killer T (NKT) cells recognize glycolipid antigens presented by the MHC class I–related glycoprotein CD1d. The in vivo dynamics of the NKT cell population in response to glycolipid activation remain poorly understood. Here, we show that a single administration of the synthetic glycolipid α-galactosylceramide (α-GalCer) induces long-term NKT cell unresponsiveness in mice. NKT cells failed to proliferate and produce IFN-γ upon α-GalCer restimulation but retained the capacity to produce IL-4. Consequently, we found that activation of anergic NKT cells with α-GalCer exacerbated, rather than prevented, B16 metastasis formation, but that these cells retained their capacity to protect mice against experimental autoimmune encephalomyelitis. NKT cell anergy was induced in a thymus-independent manner and maintained in an NKT cell–autonomous manner. The anergic state could be broken by IL-2 and by stimuli that bypass proximal TCR signaling events. Collectively, the kinetics of initial NKT cell activation, expansion, and induction of anergy in response to α-GalCer administration resemble the responses of conventional T cells to strong stimuli such as superantigens. Our findings have important implications for the development of NKT cell–based vaccines and immunotherapies.

Authors

Vrajesh V. Parekh, Michael T. Wilson, Danyvid Olivares-Villagómez, Avneesh K. Singh, Lan Wu, Chyung-Ru Wang, Sebastian Joyce, Luc Van Kaer

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Role of TCR, NK1.1, and Ly49 expression in the maintenance of NKT cell a...
Role of TCR, NK1.1, and Ly49 expression in the maintenance of NKT cell anergy. (A–C) Surface expression of TCR, NK1.1, and Ly49 molecules. Mice were injected with α-GalCer or vehicle, and spleen and liver cells were prepared at the indicated time points. Cells were stained with anti–TCR-β–FITC or –allophycocyanin, tetramer-PE, anti-B220–PerCP, and anti-NK1.1–allophycocyanin or a cocktail of FITC-labeled anti-Ly49 antibodies, and analyzed by flow cytometry. Levels of TCR expression on B220–tetramer+ cells (A), NK1.1 expression on B220–TCR-β+tetramer+ cells (B), and Ly49 expression on B220–TCR-β+tetramer+ cells (C) were evaluated. Data are representative of 4 independent experiments with 2 mice in each group. (D) Induction of NKT cell anergy in mice lacking classical MHC class I molecules. WT B6 and TAP–/– mice were injected with α-GalCer or vehicle. Fifteen days later, spleen cells were prepared and restimulated in vitro with α-GalCer (100 ng/ml). Proliferative and cytokine responses were evaluated as in Figure 1. Results shown represent the mean ± SEM of 2 mice in each group and are representative of 2 individual experiments.