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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α-GalCer induces unresponsiveness to rechallenge with this antigen in mi...
α-GalCer induces unresponsiveness to rechallenge with this antigen in mice. (A) The in vitro recall response of mice to α-GalCer immunization. Mice were injected with 5 μg α-GalCer (i.p.) and sacrificed at the indicated time points, and splenocytes (2 × 105 per well) were cultured with graded doses of α-GalCer. After 3 days, proliferation was assessed by [3H]thymidine incorporation, and culture supernatants were evaluated for IL-4 and IFN-γ levels by ELISA. Proliferation results represent the mean ± SEM of triplicate wells, and cytokine results represent the mean ± SEM of 2 mice. Representative data of 4 individual experiments are shown. (B) In vivo dynamics of the NKT cell population in response to α-GalCer (α-GC) administration. Mice were injected with α-GalCer or vehicle (veh), spleen or liver mononuclear cells were prepared at the indicated time points, and cells were stained with anti–TCR-β–FITC, tetramer-PE, and anti-B220–peridinin chlorophyll protein (anti-B220–PerCP) and analyzed by flow cytometry. Numbers indicate the percentage of TCR-β+tetramer+ cells among B220– cells. A representative of 3 separate experiments is shown. (C) Influence of the injected α-GalCer dose. Mice were treated with the indicated doses of α-GalCer and analyzed 1 month later as in A.