Little is understood regarding NK-cell functions and regulatory mechanisms

in the lung microenvironment during influenza virus infection. It has been reported that NK-cell depletion or inhibition of NK-cell function in mice can lead to worse morbidity and mortality from influenza virus infection [24-26]. Although this may be the case in mild influenza infection, in this report we demonstrate that NK cells can also be responsible Dabrafenib supplier for enhanced morbidity and mortality during more severe influenza infection, which is transferable by NK cells in mice. These results point to the complexity of NK-cell activities and possible regulatory functions of this cell type during influenza infection. NK cells not only can destroy virus-infected cells without previous stimulation, but they also can modulate the adaptive immune response [3, 16]. We were interested in determining the nature and function of NK cells in the lung during influenza virus

infections. We began by quantifying NK cells in lungs of C57BL/6 mice from day 1 to day 6 postinfection with influenza A/PR8. Compared with mock infection, influenza A/PR8 infection increased the frequency of NK cells in the lung. The percentage of CD3−NKp46+ cells in lung increased fourfold as a result of influenza infection (Fig. 1A). The majority of CD3−NKp46+ cells in influenza-infected lung were NK1.1+ and CD127− (Fig. 1A). Virus-induced NK cells PD-0332991 solubility dmso were detected in lung on days 3 and 4 postinfection, whereupon they rapidly declined (Fig. 1B). We also examined splenic NK cells

over 6 days postinfection. Lung influenza infection had no influence on the frequency or phenotype of splenic NK cells (data not shown). Despite the rise and fall of NK-cell frequency, there is progressive inflammation in the lung over 6 days of virus infection (Fig. 1C). In addition to NKp46, CD127, and NK1.1 (Figs. 1A and 2A), we characterized the phenotype and lineage markers expressed on NK cells present in influenza-infected lung. The tumor necrosis family member CD27 and integrin CD11b (Mac-1) are markers of the NK-cell lineage [27]. CD11b−CD27+, CD11b+CD27+, and CD11b+CD27− NK cells represent a progression from immature Selleck MK-3475 to mature cells with high cytolytic activity, and then to mature cells with limited lytic capability, respectively [27]. At the peak of the NK-cell response to influenza, most lung NK cells are mature CD11b+CD27− cells (Fig. 2B, upper right panel), although a small portion are CD11b+CD27+. NKG2A and Ly49C/I are inhibitory receptors expressed by C57BL/6 NK cells [7, 28]. We found that most NK cells from the lungs of influenza-infected mice express NKG2A and/or Ly49C/I, with a large percentage simultaneously expressing NKG2A and Ly49C/I, or only Ly49C/I, with much smaller percentages expressing only NKG2A, or neither receptor type (Fig. 2B, lower right panel). This pattern of NKG2A and Ly49C/I expression was similar to NK cells in the lung (Fig.