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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NKT cell anergy is cell autonomous and does not exhibit dominant suppres...
NKT cell anergy is cell autonomous and does not exhibit dominant suppression. (A) NKT cell anergy is predominantly cell autonomous. Mice were injected with α-GalCer and sacrificed at 0 days (control [C]), 3 days, 7 days, or 1 month. DCs from the spleen and NKT cells from the liver were then enriched as described in Methods. NKT cells (1 × 105 per well) and DCs (2 × 104 per well) were then cultured in different combinations in the presence (+) or absence (–) of α-GalCer. Proliferation was assessed by [3H]thymidine incorporation, and IL-4 and IFN-γ levels in the supernatant were evaluated by ELISA. (B) NKT cells remain anergic upon adoptive transfer. Mice were injected with α-GalCer or vehicle and sacrificed on day 3. NKT cells were enriched as described in Methods, and 1 × 107 cells were adoptively transferred into irradiated Jα18–/– mice. Two weeks later, mice were sacrificed; splenocytes, normalized for numbers of NKT cells, were stimulated with vehicle or α-GalCer; and then proliferative and cytokine responses were measured. No IL-4 was detected in any of the cultures. Data represent the average of 3 mice per group. (C) Anergic NKT cells fail to exhibit dominant suppression. Spleen cells from naive mice and from mice injected 1 month earlier with α-GalCer were mixed at the indicated ratios and cultured with α-GalCer (100 ng/ml), and then proliferative and cytokine responses were measured. Proliferation results represent the mean ± SEM of triplicate wells, and cytokine results represent the mean ± SEM of duplicate wells. Representative data of 3 individual experiments are shown.