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 4

H3N1-exposed NKT cells suppress AHR and increase OVA-specific Tregs.

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H3N1-exposed NKT cells suppress AHR and increase OVA-specific Tregs. (A)...
(A) Protocol for adoptive transfer of NKT cells. (B and C) Lung resistance was measured in recipient mice (B; n = 15/group) and BAL cells collected (C). (D) Relative numbers of CD4+ versus DN NKT cells in recipients’ lungs were assessed (E) H3N1-exposed CD4–CD8–NKT (vDN NKT) or CD4+NKT (vCD4 NKT) cells were purified and transferred as in A. Lung resistance was measured in recipient mice (n = 5/group). (F) Eight-week-old WT BALB/c mice received 5 × 104 DO11.10 Rag–/– T cells and were sensitized with OVA/alum. Seven days later, NKT cells from WT BALB/c, Vα14tg, or H3N1-infected mice were adoptively transferred into OVA-sensitized mice. After OVA challenge, the numbers of natural Tregs (CD4+C25+Foxp3+) and adaptive OVA antigen–specific Tregs (CD4+ CD25+ Foxp3+KJ1-26+) were determined. Absolute cell numbers were calculated (n = 5/group). (G) Eight-week-old WT BALB/c recipients were depleted of Tregs through injections of anti-CD25 mAb (clone PC61; 0.5 mg) and assessed as in A (n = 5/group). (H and I) NKT cells from WT or Vα14 Tg were transferred to OVA-sensitized BALB/c mice (n = 4–6/group), which were assessed as in A (H), and BAL cells were analyzed (I). (J) Representative lung sections from recipients described in H were H&E stained (original magnification, ×10). Data represent 2–3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001 versus WT NKT-OVA (B–D), OVA (E), WT NKT (F, H, and I), and OVA-vNKT (G).