Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice

C57BL/6 mice genetically deficient in interleukin 15 (IL-15(-/-) mice) were generated by gene targeting. IL-15(-/-) mice displayed marked reductions i n numbers of thymic and peripheral natural killer (NK) T cells, memory phen otype CD8(+) T cells, and distinct subpopulations of intestinal intraepithe lial lymphocytes (IELs). The reduction but not absence of these populations in IL-15(-/-) mice likely reflects all important role for IL-15 for expans ion and/or survival of these cells. IL-15(-/-) mice lacked NK cells, as ass essed by both immunophenotyping and functional criteria, indicating an obli gate role for IL-15 in the development and functional maturation of NK cell s. Specific defects associated with IL-15 deficiency were reversed by in vi vo administration of exogenous IL-15. Despite their immunological defects, IL-15(-/-) mice remained healthy when maintained under specific pathogen-fr ee conditions. However, IL-15(-/-) mice are likely to have compromised host defense responses to various pathogens, as they were unable to mount a pro tective response to challenge with vaccinia virus. These data reveal critic al roles for IL-15 in the development of specific lymphoid lineages. Moreov er, the ability to rescue lymphoid defects in IL-15(-/-) mice by IL-15 admi nistration represents a powerful means by which to further elucidate the bi ological roles of this cytokine.