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.
View: Text | PDF
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

×

Figure 5

The protective effect of H3N1 infection depends on TLR7 and T-bet.

Options: View larger image (or click on image) Download as PowerPoint
The protective effect of H3N1 infection depends on TLR7 and T-bet. (A) S...
(A) Schematic showing the protocol for WT, Tlr7–/–, or Tbet–/– mice infected at 2 weeks of age with H3N1 virus or mock infected and examined for OVA-induced AHR at 8 weeks of age (n = 4–6 per group). (B) Lung resistance was measured. *P < 0.05, **P < 0.01, ***P < 0.001 compared with the mock-OVA group. (C) BAL cells from B were collected. (D) WT, Tlr7–/–, or Tbet–/– mice were infected with H3N1 or mock at 2 weeks of age, and lung samples were taken 42 days later to asses for NKT cell subsets. ***P < 0.001 compared with the mock group. (E) Schematic showing the adoptive transfer of NKT from virus-infected WT, Tlr7–/–, or Tbet–/– mice to OVA-sensitized BALB/c recipients (n = 4–6 per group). The donor mice were infected with H3N1 or mock-infected at 2 weeks of age. NKT cells were purified from these mice 42 days after infection and transferred to OVA-sensitized BALB/c mice, which were then challenged with OVA to induce AHR. (F) Left: After OVA challenge, AHR was measured as described in D. Right: Cells in BAL were assessed. ***P < 0.001 compared with the WT-OVA group. Data are representative of 2 independent experiments.