This may include regulation of T cell differentiation from na?ve precursors and contribution to inflammation during the effector phases. secretion of the Th2 cytokines IL-4, Minoxidil (U-10858) IL-5 and IL-13 and diminished OVA-specific antibody production. Furthermore, while OVA-exposure induced a dramatic growth of dendritic cells (DCs) in WT mice, their induction was significantly attenuated in NKD mice. Development of OVA-AAD in perforin?/? mice suggested that this proinflammatory role of NK cells is not dependent on perforin-mediated cytotoxicity. Lastly, induction of allergic disease by OVA-specific CD4 T cells from WT Rabbit Polyclonal to p19 INK4d but not NK-depleted or NKD mice in RAG?/? recipients, demonstrates that NK cells are essential for T cell priming. Conclusions and Clinical Relevance Our data demonstrate that standard NK cells play an important and distinct role in the development of AAD. The presence of activated NK cells has been noted in patients with asthma. Understanding the mechanisms by which NK cells regulate allergic disease is usually therefore an important component of treatment methods. INTRODUCTION Asthma is usually a chronic inflammation of the airways manifested as reversible airway obstruction, increased eosinophilic inflammation and airway hyperreactivity. T lymphocytes of the Th2 subset and their cytokines IL-4, IL-5 and IL-13 are pivotal in the development of asthma pathogenesis [1C7]. However, other types of immune cells including NK and NKT cells may also contribute to allergic inflammation [8C11]. NK cells participate at various levels in the generation of immune responses. This includes cytotoxic effector functions against virally infected and transformed cells [12, 13], the ability to modulate cytokine and chemokine environments [14], and induction of DC maturation [15]. These activities are mediated by cognate interactions inhibitory and stimulatory receptors [16]. NKT cells, a subset of cells bearing T cell receptors with restricted heterogeneity and expressing NK cell markers (NK1.1 in C57BL/6 mice) Minoxidil (U-10858) [17, 18] can also play comparable functions [19, 20]. In light of the various immunomodulatory effects exhibited by NK cells, we sought to examine whether these cells play a role in the development of allergic airway disease (AAD) in mice. Previous studies have suggested a role for NK cells in allergic inflammation in patients Minoxidil (U-10858) with asthma [21C23]. Similarly, depletion of NK and NKT cells using the pan-NK1.1 specific antibody, suggested that these cells can regulate the development of airway eosinophilia in C57BL/6 mice [9]. However, both NK and NKT cells were depleted in the above study, and due to the lack of animals with selective deficiencies in NK cells as well as observations that NKT cells can also regulate allergic inflammation [8, 10, 24], the specific contribution of NK cells has not been well-established. In order to specifically address the role of NK cells in AAD, we studied the development of Minoxidil (U-10858) OVA-induced AAD in mice with selective deficiencies in the NK cell compartment (NKD mice), and in mice depleted of specific NK cell subsets using monoclonal antibodies reactive against Ly49 receptors. NKD mice are transgenic mice expressing the Ly49A inhibitory receptor under control of the granzyme A promoter [25, 26]. While these mice have functionally normal T, B and NKT cells, they have a profound deficiency in NK cells in peripheral organs, which translates into a functional impairment of NK cells [27C29]. Expression of the transgene does not have endogenous functional consequences, since the ligand for Ly49A is usually H-2Dd, which is usually expressed in BALB/c mice. We show that this development of OVA-AAD was significantly inhibited in NKD mice as evidenced by an overall decrease in inflammation and eosinophilia in the BAL and lungs, decrease of OVA-specific IgE antibodies, and decreased production of Th2 cytokines in the airways. Similarly, Ly49A/D/G-depleted mice, a model that preferentially depletes specific subsets of standard NK cells, also showed an inhibition of features of OVA-AAD. Exposure to OVA sensitization and challenge induced a dramatic growth in the numbers of spleen and airway DCs, which was significantly attenuated in NKD mice. Furthermore, inhibition of airway inflammation in this model was not dependent on perforin-mediated NK cell cytotoxicity. Lastly, adoptive transfer experiments confirm the requirement for NK cells during OVA-AAD, and establish their effects during T cell priming. Our observations thus elucidate for the first time the specific role of standard NK cells in the OVA model of AAD.
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