Title

Pro-inflammatory role of natural killer cells in the development of allergic airway disease

Date of Completion

January 2005

Keywords

Health Sciences, Pathology|Health Sciences, Immunology

Degree

Ph.D.

Abstract

Natural Killer (NK) cells have the potential to modulate adaptive immune responses. We investigated the role of NK cells in an ovalbumin (OVA) based model of AAD using NK-deficient (NKD) mice and immunodepletion experiments. Induction of AAD in NKD mice and in mice depleted of NK cells expressing Ly49 A, D, G receptors resulted in attenuation of airway eosinophilia, Th2 cytokine production and lung histopathology. Adoptive transfer experiments further confirmed the role of NK cells and showed that they were especially important during the priming phase of the AAD model. We found both NK and NKT cells in the lung tissue and BAL of wild type mice during AAD. The lung NKT cells were activated immediately after sensitization, suggesting that they may also contribute to AAD. However, attenuation of AAD in NKD mice which are deficient in NK cells but have normal NKT cell numbers suggested that they were not essential for AAD in our model. This was further corroborated by development of AAD in β2m and CD Id knock-out (KO) mice which are also deficient in NKT cells. We examined perforin KO mice to determine the role of NK cells. Development of disease in these mice indicated that NK cell perforin-mediated cytotoxicity was not essential in AAD regulation. The effects of NK cells on other cells were determined by examining dendritic cells (DCs) in wild type and NKD mice during AAD. Decreased numbers of DCs in the lungs of NKD mice during AAD suggested that NK-DC interactions may play a role in AAD regulation. The effect of cytokines important in AAD development was determined using IL-15 and IL-15Rα KO mice which are deficient in NK, NKT, γδ T and memory CD8 T cells. Both IL-15 and IL-15Rα KO mice were susceptible to AAD. Interestingly, IL-15 KO mice also developed enhanced expression of the disease. Based on the above results, we conclude that NK cells play a pro-inflammatory role in the development of AAD. While they are important for the allergic phenotype, they are not absolutely essential as suggested by the demonstration of AAD in mice deficient in IL-15 interactions. ^