Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity; however, their function during rhinovirus infection in vivo is undefined. In RV-infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expressions of IL-15 and IL-15Ralpha, which in turn were required for NK- and CD8(+) T-cell responses. Treatment with IL-15-IL-15Ralpha complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Ralpha, IFN-gamma, CXCL9, and CXCL10 followed by recruitment of activated, IFN-gamma-expressing NK, CD8(+), and CD4(+) T cells. Treating infected IFNAR1(-/-) mice with IL-15c similarly increased IL-15, IL-15Ralpha, IFN-gamma, and CXCL9 (but not CXCL10) expression also followed by NK-, CD8(+)-, and CD4(+)-T-cell recruitment and activation. We have demonstrated that type I IFN-induced IFN-gamma and cellular immunity to RV was mediated by IL-15 and IL-15Ralpha. Importantly, we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment, which in turn was sufficient to drive IFN-gamma expression and lymphocyte responses.