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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Role of distinct APCs and cytokines in the induction of NKT cell anergy....
Role of distinct APCs and cytokines in the induction of NKT cell anergy. (A) Role of distinct APCs. Mice were treated with α-GalCer–pulsed or –unpulsed DCs (6 × 105 cells per mouse, i.v.) or B cells (5 × 106 cells per mouse, i.v.) and sacrificed 15 days later, and spleen cells were restimulated with or without α-GalCer (100 ng/ml). Proliferation was assessed by [3H]thymidine incorporation, and IL-4 and IFN-γ levels in the supernatant were evaluated by ELISA. Results shown represent the mean ± SEM of 4 mice in each group and are representative of 2 individual experiments. (B) Role of cytokines. WT B6, IL-10–/–, IFN-γ–/–, and IL-4–/– mice were injected with α-GalCer or vehicle, sacrificed 15 days later, and analyzed as in A. Results shown represent the mean ± SEM of 2 mice in each group.