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Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity
Ya-Jen Chang, … , Petr Illarionov, Dale T. Umetsu
Ya-Jen Chang, … , Petr Illarionov, Dale T. Umetsu
Published December 13, 2010
Citation Information: J Clin Invest. 2011;121(1):57-69. https://doi.org/10.1172/JCI44845.
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Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity

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Abstract

Infection with influenza A virus represents a major public health threat worldwide, particularly in patients with asthma. However, immunity induced by influenza A virus may have beneficial effects, particularly in young children, that might protect against the later development of asthma, as suggested by the hygiene hypothesis. Herein, we show that infection of suckling mice with influenza A virus protected the mice as adults against allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma. The protective effect was associated with the preferential expansion of CD4–CD8–, but not CD4+, NKT cells and required T-bet and TLR7. Adoptive transfer of this cell population into allergen-sensitized adult mice suppressed the development of allergen-induced AHR, an effect associated with expansion of the allergen-specific forkhead box p3+ (Foxp3+) Treg cell population. Influenza-induced protection was mimicked by treating suckling mice with a glycolipid derived from Helicobacter pylori (a bacterium associated with protection against asthma) that activated NKT cells in a CD1d-restricted fashion. These findings suggest what we believe to be a novel pathway that can regulate AHR, and a new therapeutic strategy (treatment with glycolipid activators of this NKT cell population) for asthma.

Authors

Ya-Jen Chang, Hye Young Kim, Lee A. Albacker, Hyun Hee Lee, Nicole Baumgarth, Shizuo Akira, Paul B. Savage, Shin Endo, Takashi Yamamura, Janneke Maaskant, Naoki Kitano, Abel Singh, Apoorva Bhatt, Gurdyal S. Besra, Peter van den Elzen, Ben Appelmelk, Richard W. Franck, Guangwu Chen, Rosemarie H. DeKruyff, Michio Shimamura, Petr Illarionov, Dale T. Umetsu

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Figure 7

PI57 directly activates NKT cells.

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PI57 directly activates NKT cells.
(A) NKT cell lines were cocultured wi...
(A) NKT cell lines were cocultured with BM-derived DCs (BMDCs) and α-GalCer (100 ng/ml), PI57 (10 μg/ml), or vehicle for 48 hours, with or without pre-incubation with anti-CD1d (10 μg/ml). IFN-γ was measured by ELISA. (B) Murine NKT cell lines were cocultured as in A with BMDCs from WT, Cd1d–/–, Myd88–/–, or Trif–/– mice. Cells were treated with α-GalCer (100 ng/ml), PI57 (2.5, 5, or 10 μg/ml), PBS30 (1, 2.5, or 5 μg/ml), or vehicle for 48 hours. IFN-γ and IL-4 were measured by ELISA. (C) IL-2 production from hybridomas derived from invariant Vα14 NKT cells (RT2, RT23, and RT24) and an irrelevant Vβ8+ T cell (RT8; control) (see Supplemental Methods). (D) Mouse NKT cell lines were stained with PE-labeled CD1d tetramers of PI57 or α-GalCer at 4°C for 45 minutes or 37°C for 25 minutes, and with anti-TCRβ–APC antibody. Top: Lymphocytes were gated in the FSC/SSC window. Bottom: Percentage of CD1d tetramer+ cells. (E) IFN-γ and IL-4 production from human NKT cell lines by treatment with α-GalCer (100 ng/ml), PI57 (10 μg/ml), or vehicle for 48 hours in vitro (see Supplemental Methods). (F) IFN-γ production from CD1d-transfected NKT cell clone BM2a.3 in presence of PI57 and blocking mAb against human CD1d or CD1b (see Supplemental Methods). (G) CD1d Fc-coated Maxisorp plates were loaded with lipid and cultured with 5 × 104 NKT cells. IFN-γ was analyzed by ELISA after 24 hours. Data represent 3 or 5 independent experiments.

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