IL-15 is a novel cytokine with potent T cell growth factor activity. Here, we investigated the role of IL-15 in the human immune response to intracellular infection by studying patients leprosy. We found that IL-15 mRNA and protein were more strongly expressed in immunologically resistant tuberculoid patients than in with unresponsive and susceptible lepromatous patients. In vitro, Mycobacterium leprae induced IL-15 secretion from peripheral blood monocytes. Furthermore, rIL-15 by itself and in combination with rIL-2 or rIL-7 augmented PBMC proliferative responses to the pathogen. Although rIL-15 expanded the CD3-CD56+ (NK) subset, rIL-15 combined with M. leprae induced the expansion of CD3+CD56+ T cells. Immunohistologic analysis of leprosy skin lesions indicated that the frequency of CD56+ cells was greatest in the group of patients with high IL-15 expression, and that >90% of the CD56+ cells in lesions were CD3+ T cells. Therefore, IL-15 augments the local T cell response to human intracellular pathogen.