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

Parekh VV, Wilson MT, Olivares-Villagómez D, Singh AK, Wu L, Wang CR, Joyce S, Van Kaer L
J Clin Invest. 2005 115 (9): 2572-83

PMID: 16138194 · PMCID: PMC1193878 · DOI:10.1172/JCI24762

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 alpha-galactosylceramide (alpha-GalCer) induces long-term NKT cell unresponsiveness in mice. NKT cells failed to proliferate and produce IFN-gamma upon alpha-GalCer restimulation but retained the capacity to produce IL-4. Consequently, we found that activation of anergic NKT cells with alpha-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 alpha-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.

MeSH Terms (17)

Animals Clonal Anergy Female Galactosylceramides Humans Interferon-gamma Interleukin-2 Interleukin-4 Killer Cells, Natural Liver Lung Neoplasms Lymphocyte Activation Mice Mice, Inbred C57BL Receptors, Antigen, T-Cell Signal Transduction Spleen

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