Glycolipid antigen induces long-term natural killer T cell anergy in mice
Vrajesh V. Parekh, Michael T. Wilson, Danyvid Olivares-Villagómez, Avneesh K. Singh, Lan Wu, Chyung-Ru Wang, Sebastian Joyce, Luc Van Kaer
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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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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Anergic NKT cells are unable to protect mice against lung melanoma metas...
Anergic NKT cells are unable to protect mice against lung melanoma metastases but retain their capacity to prevent EAE. (A) Determination of B16 tumor lung metastasis formation. B6 mice were treated with α-GalCer or vehicle, and, 1 month later, mice were challenged i.v. with 3 × 105 B16 melanoma cells and treated with α-GalCer (5 μg/injection) or vehicle at 0, 4, and 8 days after the tumor challenge. Mice were sacrificed after 15 days, and the number of metastatic nodules was counted in the lungs. Results shown are the average of 2 experiments with 6 mice in each group per experiment and are representative of a total of 3 experiments with a total of at least 18 mice in each group. Representative photographs of lungs from these animals are shown in Supplemental Figure 2. (B) Modulation of EAE. B6 mice were treated with α-GalCer or vehicle, and, 1 month later, EAE was induced. Mice were treated with α-GalCer (5 μg/injection) or vehicle on days 0, 4, and 7. Data shown represent the average values of 2 experiments with the number of mice indicated in each group. Data and statistical values are summarized in Supplemental Table 1.