Impact of bacteria on the phenotype, functions, and therapeutic activities of invariant NKT cells in mice
Sungjune Kim, … , Lan Wu, Luc Van Kaer
Sungjune Kim, … , Lan Wu, Luc Van Kaer
Published May 1, 2008
Citation Information: J Clin Invest. 2008;118(6):2301-2315. https://doi.org/10.1172/JCI33071.
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Impact of bacteria on the phenotype, functions, and therapeutic activities of invariant NKT cells in mice

Abstract

Invariant NKT (iNKT) cells are innate-like lymphocytes that recognize glycolipid antigens in the context of the MHC class I–like antigen-presenting molecule CD1d. In vivo activation of mouse iNKT cells with the glycolipid α-galactosylceramide (α-GalCer) results in the acquisition of a hyporesponsive (anergic) phenotype by these cells. Because iNKT cells can become activated in the context of infectious agents, here we evaluated whether iNKT cell activation by microorganisms can influence subsequent responses of these cells to glycolipid antigen stimulation. We found that mouse iNKT cells activated in vivo by multiple bacterial microorganisms, or by bacterial LPS or flagellin, became unresponsive to subsequent activation with α-GalCer. This hyporesponsive phenotype of iNKT cells required IL-12 expression and was associated with changes in the surface phenotype of these cells, reduced severity of concanavalin A–induced hepatitis, and alterations in the therapeutic activities of α-GalCer. These findings may have important implications for the development of iNKT cell–based therapies.

Authors

Sungjune Kim, Saif Lalani, Vrajesh V. Parekh, Tiffaney L. Vincent, Lan Wu, Luc Van Kaer

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Figure 5

Bacteria can induce iNKT cell hyporesponsiveness to α-GalCer rechallenge in vivo.

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Bacteria can induce iNKT cell hyporesponsiveness to α-GalCer rechallenge...
(A, C, E, and G) At the indicated times after injection with heat-killed E. coli (A), live L. monocytogenes (C), heat-killed S. aureus (E), or heat-killed S. typhimurium (G), mice were rechallenged in vivo with vehicle or α-GalCer (1 μg/mouse, i.p.). Mice were sacrificed 3 days later, and spleen cells were stained with anti–TCR-β–FITC, anti-B220–PerCP, and tetramer-allophycocyanin and analyzed by flow cytometry. Numbers indicate the percentage of TCR-β+tetramer cells among B220– cells. Data represent results obtained in at least 2 separate experiments involving 5–7 mice per group. (B, D, F, and H) Total spleen iNKT cells calculated from the experiments shown in A, C, E, and G, respectively. *P < 0.05 compared with naive mice rechallenged with α-GalCer. (I) Hyporesponsive iNKT cells are defective in transactivating B cells, DCs, and NK cells in vivo. Mice were injected with the indicated bacteria and rechallenged with α-GalCer (1 μg/mouse, i.p) 3 weeks later. Mice were then sacrificed at the 24-hour time point, and spleen mononuclear cells were stained with different combinations of anti-CD86–PE, anti-B220–PerCP, anti-CD11c–allophycocyanin, anti-CD69–FITC, anti-NK1.1–allophycocyanin, and anti–TCR-β–PE. For IFN-γ staining on NK cells, mice were sacrificed 6 hours following α-GalCer rechallenge, and spleen mononuclear cells were cultured 2 hours in the presence of GolgiPlug. Cells were then stained with anti–IFN-γ–FITC, anti-NK1.1–allophycocyanin, and anti–TCR-β–PE. Data shown are representative of 6 mice per group from 2 separate experiments.