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Natural killer cells determine development of allergen-induced eosinophilic airway inflammation in mice.

Korsgren M, Persson CG, Sundler F, Bjerke T, Hansson T, Chambers BJ, Hong S, Van Kaer L, Ljunggren HG, Korsgren O - J. Exp. Med. (1999)

Bottom Line: 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.Depletion of NK1.1(+) cells during the challenge period only did not influence pulmonary eosinophilic inflammation.These observations are also compatible with a pathogenic role for the increased NK cell activity observed in human asthma.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Neuroscience, Lund University Hospital, 221 85 Lund, Sweden. Magnus.Korsgren@mphy.lu.se

ABSTRACT
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 gamma/delta 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 gamma-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 gamma/delta 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.

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Effect of depleting NK1.1+ cells before immunization on  BALF cytokine levels 8 h after last OVA or SAL exposure. Mice were  immunized on day 0 and challenged daily with aerosolized OVA or SAL  on days 14–20. Solid bars, mean (n = 5–8 per group); OVA, OVA-challenged animals; SAL, SAL-challenged animals; IgG, IgG-treated animals;  NK1.1, mAb NK1.1–treated animals. Dotted lines, detection limit of the  assays. *P < 0.05, ***P < 0.001.
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Figure 3: Effect of depleting NK1.1+ cells before immunization on BALF cytokine levels 8 h after last OVA or SAL exposure. Mice were immunized on day 0 and challenged daily with aerosolized OVA or SAL on days 14–20. Solid bars, mean (n = 5–8 per group); OVA, OVA-challenged animals; SAL, SAL-challenged animals; IgG, IgG-treated animals; NK1.1, mAb NK1.1–treated animals. Dotted lines, detection limit of the assays. *P < 0.05, ***P < 0.001.

Mentions: To determine the type of immune response (Th1 and/or Th2) being induced in the airways of immunized mice after multiple allergen aerosol exposures, we measured cytokines in BALF taken 8 h after last aerosol exposure. The levels of IL-4 in BALF were similar in both IgG-treated and NK1.1+ cell–depleted mice receiving seven OVA challenges compared with corresponding SAL-exposed animals (Fig. 3). Thus, the increased levels demonstrated after two OVA exposures in immunized IgG-treated mice (but not in corresponding mice depleted of NK1.1+ cells) were not detected under these more chronic conditions. BALF from IgG-treated mice receiving seven allergen challenges contained measurable amounts of IL-5 (P < 0.05, compared with SAL-exposed IgG-treated animals; Fig. 3). In contrast, NK1.1+ cell–depleted animals failed to release IL-5 after OVA exposure (Fig. 3). The levels of IL-12 in BALF increased after allergen exposure in IgG-treated animals (P < 0.001, compared with corresponding SAL-challenged animals; Fig. 3). In contrast, IL-12 levels in BALF from NK1.1+ cell–depleted mice remained low in response to allergen exposure, similar to the levels in corresponding SAL-exposed animals. The levels of IFN-γ in BALF decreased after allergen challenge to values very near or below the detection limit of the assay in five out of seven IgG-treated animals (Fig. 3). Interestingly, the two animals exhibiting high IFN-γ values showed undetectable IL-5 levels in BALF and no pulmonary eosinophilia. OVA challenge of mice depleted of NK1.1+ cells caused a moderate decrease in levels of IFN-γ (P < 0.05, compared with corresponding SAL-exposed mice; Fig. 3).


Natural killer cells determine development of allergen-induced eosinophilic airway inflammation in mice.

Korsgren M, Persson CG, Sundler F, Bjerke T, Hansson T, Chambers BJ, Hong S, Van Kaer L, Ljunggren HG, Korsgren O - J. Exp. Med. (1999)

Effect of depleting NK1.1+ cells before immunization on  BALF cytokine levels 8 h after last OVA or SAL exposure. Mice were  immunized on day 0 and challenged daily with aerosolized OVA or SAL  on days 14–20. Solid bars, mean (n = 5–8 per group); OVA, OVA-challenged animals; SAL, SAL-challenged animals; IgG, IgG-treated animals;  NK1.1, mAb NK1.1–treated animals. Dotted lines, detection limit of the  assays. *P < 0.05, ***P < 0.001.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2192913&req=5

Figure 3: Effect of depleting NK1.1+ cells before immunization on BALF cytokine levels 8 h after last OVA or SAL exposure. Mice were immunized on day 0 and challenged daily with aerosolized OVA or SAL on days 14–20. Solid bars, mean (n = 5–8 per group); OVA, OVA-challenged animals; SAL, SAL-challenged animals; IgG, IgG-treated animals; NK1.1, mAb NK1.1–treated animals. Dotted lines, detection limit of the assays. *P < 0.05, ***P < 0.001.
Mentions: To determine the type of immune response (Th1 and/or Th2) being induced in the airways of immunized mice after multiple allergen aerosol exposures, we measured cytokines in BALF taken 8 h after last aerosol exposure. The levels of IL-4 in BALF were similar in both IgG-treated and NK1.1+ cell–depleted mice receiving seven OVA challenges compared with corresponding SAL-exposed animals (Fig. 3). Thus, the increased levels demonstrated after two OVA exposures in immunized IgG-treated mice (but not in corresponding mice depleted of NK1.1+ cells) were not detected under these more chronic conditions. BALF from IgG-treated mice receiving seven allergen challenges contained measurable amounts of IL-5 (P < 0.05, compared with SAL-exposed IgG-treated animals; Fig. 3). In contrast, NK1.1+ cell–depleted animals failed to release IL-5 after OVA exposure (Fig. 3). The levels of IL-12 in BALF increased after allergen exposure in IgG-treated animals (P < 0.001, compared with corresponding SAL-challenged animals; Fig. 3). In contrast, IL-12 levels in BALF from NK1.1+ cell–depleted mice remained low in response to allergen exposure, similar to the levels in corresponding SAL-exposed animals. The levels of IFN-γ in BALF decreased after allergen challenge to values very near or below the detection limit of the assay in five out of seven IgG-treated animals (Fig. 3). Interestingly, the two animals exhibiting high IFN-γ values showed undetectable IL-5 levels in BALF and no pulmonary eosinophilia. OVA challenge of mice depleted of NK1.1+ cells caused a moderate decrease in levels of IFN-γ (P < 0.05, compared with corresponding SAL-exposed mice; Fig. 3).

Bottom Line: 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.Depletion of NK1.1(+) cells during the challenge period only did not influence pulmonary eosinophilic inflammation.These observations are also compatible with a pathogenic role for the increased NK cell activity observed in human asthma.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Neuroscience, Lund University Hospital, 221 85 Lund, Sweden. Magnus.Korsgren@mphy.lu.se

ABSTRACT
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 gamma/delta 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 gamma-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 gamma/delta 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.

Show MeSH
Related in: MedlinePlus