Because we have previously reported that IL-15 is important for the migration of influenza-specific CD8 T cells into the lung airways [19] , it was possible that those observed effects were secondary to the recruitment of NK cells to the lung. To test whether the accumulation of NK cells in the lung was required for the subsequent immigration of influenza-specific CD8 T cells to the respiratory tract, influenza-infected animals were assayed for the accumulation of anti-influenza specific CD8 T cells in NK deficient animals, generated by administration of the aNK1.1 depleting mAb PK136 every other day ( Figure 6A ). Flow cytometric analyses of NKp46 expression of day 4 p.i. lymphocytes isolated from the lung, BAL, spleen, and mediastinal lymph nodes (MdLN) of aNK1.1-treated animals revealed robust depletion of NK cells as the number of CD3 2 NKp46 + cells were reduced to less than one third of those observed in PBS-treated control animals ( Figure 6B and data not shown). On days 6 and 8 p.i., the numbers of influenza-specific CD8 T cells in these same tissues were quantified through the identification of cells staining positive for a tetrameric reagent loaded with the immunodominant peptide derived from the influenza nucleoprotein (NP). Tetramer positive CD8 T cells could first be detected in the lung airways at day 6 p.i., and although numbers were low, they were somewhat reduced in the BAL of PK136-treated mice ( Figure 6C ). No reduction in influenza-specific CD8 T cell numbers could be observed in any other tissue. In fact, CD8 T cells seemed to accumulate in other tissues of animals depleted of NK1.1expressing cells. By day 8 p.i., the frequency of influenza-specific CD8 T cells in the BAL of PK136-injected animals was less than half than that of control animals, and the total numbers were reduced nearly threefold ( Figure 6D ). Again, this effect was specific to the lung airways, since frequencies and numbers of NPtetramer + CD8 T cells were unchanged in other tissues examined ( Figure 6D ). Therefore, the largely tissue-specific nature of the dependence of influenza-specific CD8 T cells on the presence of NK1.1-expressing cells in the lung airways partially indicates that lung-resident NK and possibly NKT cells are requisite for the subsequent migration of influenza-specific CD8 T cells into this site. These data suggest that IL-15-mediated migration of CD8 T cells to the lung airways may be, at least partially, an indirect effect of NK1.1 + cells moving into the lung airway space in response to IL-15 and that subsequent tissue remodeling or production of an intermediate factor is responsible for the subsequent recruitment of the CD8 T cells. To our knowledge, these data for the first time describe a role for IL-15 in linking the innate and adaptive responses to influenza infection necessitating the further inquiry of IL-15 as a potential vaccine adjuvant.