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Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity

Nature Medicine volume 9, pages 582–588 (2003)Cite this article

Abstract

Using natural killer T (NKT) cell–deficient mice, we show here that allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma, does not develop in the absence of Vα14i NKT cells. The failure of NKT cell–deficient mice to develop AHR is not due to an inability of these mice to produce type 2 T-helper (Th2) responses because NKT cell–deficient mice that are immunized subcutaneously at non-mucosal sites produce normal Th2-biased responses. The failure to develop AHR can be reversed by the adoptive transfer of tetramer-purified NKT cells producing interleukin (IL)-4 and IL-13 to Ja281−/− mice, which lack the invariant T-cell receptor (TCR) of NKT cells, or by the administration to Cd1d−/− mice of recombinant IL-13, which directly affects airway smooth muscle cells. Thus, pulmonary Vα14i NKT cells crucially regulate the development of asthma and Th2-biased respiratory immunity against nominal exogenous antigens. Therapies that target Vα14i NKT cells may be clinically effective in limiting the development of AHR and asthma.

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Figure 1: Analysis of antigen-induced airway responses in Cd1d1−/− mice.
Figure 2: Ja281−/− mice do not develop AHR.
Figure 3: Comparison of cytokine production, BAL fluid and IgE in Ja281−/− and BALB/c mice.
Figure 4: Adoptive transfer of NKT cells restores AHR in Ja281−/− mice.
Figure 5: IL-4 and IL-13 production by NKT cells is required for development of AHR.

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Acknowledgements

We thank R. Blumberg for discussions, A. McKenzie for reagents, V.P. Yeung for technical support, and J. Faul, S. Galli and M. Tsai for help with the invasive measurement of AHR. These studies were supported by National Institutes of Health Public Health Service Grants RO1 AI26322 (D.T.U.), RO1 HL62348 (D.T.U.), RO1 CA52511 (M.K), AI40171 (M.J.G) and GM62135 (M.J.G); a grant from the American Lung Association of California (O.A.); fellowship STO 467/2-1 from the Deutsche Forschungsgemeinschaft (P.S.); and training grant T32AI07290 (E.M.).

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Authors and Affiliations

  1. Division of Immunology and Allergy, Department of Pediatrics, Stanford University, Stanford, California, USA

    Omid Akbari, Philippe Stock, Everett Meyer, Rosemarie H. DeKruyff & Dale T. Umetsu

  2. Division of Developmental Immunology, La Jolla Institute for Allergy & Immunology, San Diego, California, USA

    Mitchell Kronenberg & Stephane Sidobre

  3. Graduate School of Medicine, Chiba University, Chiba, Japan

    Toshinori Nakayama & Masaru Taniguchi

  4. School of Public Health, Harvard University, Boston, Massachusetts, USA

    Michael J. Grusby

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Akbari, O., Stock, P., Meyer, E. et al. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat Med 9, 582–588 (2003). https://doi.org/10.1038/nm851

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