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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Research Article

Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity

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 6

Induction of protection with α-C-GalCer and a glycolipid from H. pylori.

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Induction of protection with α-C-GalCer and a glycolipid from H. pylori....
(A) Two-week-old BALB/c mice (n = 6–8/group) or (B) Tbet–/– mice (n = 4–6 per group) received 5 μg α-GalCer (cGal), 2 μg α-GalCer, or vehicle. After OVA sensitization and challenge, AHR was measured on day 44. (C) Donor mice were treated with α-C-GalCer (5 μg) or vehicle i.p. NKT cells served as donors, as in Figure 4A (n = 4 per group). Lung resistance (left) and cell counts in BAL (right) were assessed. (D) Structure of PI57. (E) Mice received PI57 (50 μg), α-GalCer (2 μg), or vehicle i.p., and lungs were examined 1 or 14 days later for CD4 and CD8 expression. (F) Absolute numbers of CD4+ NKT and DN NKT subsets from E were assessed. (G) BALB/c mice (n = 5–8/group) received PI57 or vehicle i.p. Lung resistance (left) and BAL cells (right) were assessed. (H) BALB/c mice treated with PI57 (50 μg), PBS30 (Sphingomonas glycolipid) (50 μg), or vehicle i.p. were assessed for AHR as in G. (I) Donor mice were treated with PI57 (50 μg) or vehicle i.p. NKT cells served as donors as in Figure 4A. Lung resistance (left) and BAL cells (right) were assessed (n = 4 per group). (J) Representative lung sections from I stained with H&E (original magnification, ×10). Data represent 2–3 independent experiments. *P < 0.05, #P < 0.05, ***P < 0.001 versus vehicle-OVA (C, G, and I), DN NKT saline (F), and CD4+ NKT saline (F).