<jats:title>Abstract</jats:title> <jats:p>Interleukin-15 is a pleiotropic cytokine critical for the development of multiple hematopoietic lineages. Mice lacking IL-15 have selective defects in populations of several pro-allergic immune cells including natural killer (NK) cells, NKT cells, and memory CD8+T cells. We therefore hypothesized that IL-15−/− mice will have reduced inflammatory responses during the development of allergic airway disease (AAD). Here we report that IL-15−/− mice developed enhanced allergic responses in an OVA-induced model of AAD. C57BL/6 wild-type (WT) and IL-15−/− mice were sensitized and challenged with ovalbumin (OVA) and the development of AAD was ascertained. In the absence of IL-15, OVA-challenged mice exhibited enhanced bronchial eosinophilic inflammation, elevated IL-13 production, and severe lung histopathology in comparison with WT mice. In addition, increased numbers of CD4+T and B cells in the spleens and broncholaveolar lavage were also observed. Examination of OVA-challenged IL-15R−/− animals revealed a similar phenotype resulting in enhanced airway eosinophilia compared to WT mice. Adoptive transfer of splenic CD8+T cells from OVA-sensitized WT mice suppressed the enhancement of eosinophilia in IL-15−/− animals to levels observed in WT mice, but had no further effects. These data demonstrate that mice with an endogenous IL-15 deficiency are susceptible to the development of severe, enhanced Th2-mediated AAD. Furthermore, the development of disease as well as allergen-specific Th2 responses occurs despite deficiencies in several IL-15-dependent cell types including NK and NKT cells, suggesting that these cells or their subsets are dispensable for the induction of AAD in IL-15-deficient mice.</jats:p>