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Magnus Korsgren^*, Carl G.A. Persson, Frank Sundler^*, Torbjörn Bjerke, Tony Hansson^**, Benedict J. Chambers^||, Seokmann Hong^¶, Luc Van Kaer^¶, Hans-Gustaf Ljunggren^||, and Olle Korsgren^**

From the ^* Department of Physiology and Neuroscience, and Department of Clinical Pharmacology, Lund University Hospital, 221 85 Lund, Sweden; Department of Inflammation Pharmacology, Astra Draco, 221 00 Lund, Sweden; ^|| Microbiology and Tumor Biology Center, Karolinska Institute, 171 77 Stockholm, Sweden; ^¶ Howard Hughes Medical Institute, Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and ^** Department of Clinical Immunology and Transfusion Medicine, Uppsala University Hospital, 751 85 Uppsala, Sweden

The earliest contact between antigen and the innate immune system is thought to direct the subsequent antigen-specific T cell response. We hypothesized that cells of the innate immune system, such as natural killer (NK) cells, NK1.1⁺ T cells (NKT cells), and / T cells, may regulate the development of allergic airway disease. We demonstrate here that depletion of NK1.1⁺ cells (NK cells and NKT cells) before immunization inhibits pulmonary eosinophil and CD3⁺ T cell infiltration as well as increased levels of interleukin (IL)-4, IL-5, and IL-12 in bronchoalveolar lavage fluid in a murine model of allergic asthma. Moreover, systemic allergen-specific immunoglobulin (Ig)E and IgG2a levels and the number of IL-4 and interferon –producing splenic cells were diminished in mice depleted of NK1.1⁺ cells before the priming regime. Depletion of NK1.1⁺ cells during the challenge period only did not influence pulmonary eosinophilic inflammation. CD1d1 mutant mice, deficient in NKT cells but with normal NK cells, developed lung tissue eosinophilia and allergen-specific IgE levels not different from those observed in wild-type mice. Mice deficient in / T cells showed a mild attenuation of lung tissue eosinophilia in this model. Taken together, these findings suggest a critical role of NK cells, but not of NKT cells, for the development of allergen-induced airway inflammation, and that this effect of NK cells is exerted during the immunization. If translatable to humans, these data suggest that NK cells may be critically important for deciding whether allergic eosinophilic airway disease will develop. These observations are also compatible with a pathogenic role for the increased NK cell activity observed in human asthma.

Key Words: natural killer cells • NK1.1⁺ T cells • / T cells • eosinophils • allergic asthma

Abbreviations used: BAL, bronchoalveolar lavage; BALF, BAL fluid; ELISPOT, enzyme-linked immunospot; NKT cells, NK1.1⁺ T cells; SAL, saline; SFC, spot-forming cell.

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