Reversible Defects in Natural Killer and Memory Cd8 T Cell Lineages in Interleukin 15–Deficient Mice

Abstract

C57BL/6 mice genetically deficient in interleukin 15 (IL-15−/− mice) were generated by gene targeting. IL-15−/− mice displayed marked reductions in numbers of thymic and peripheral natural killer (NK) T cells, memory phenotype CD8+ T cells, and distinct subpopulations of intestinal intraepithelial lymphocytes (IELs). The reduction but not absence of these populations in IL-15−/− mice likely reflects an important role for IL-15 for expansion and/or survival of these cells. IL-15−/− mice lacked NK cells, as assessed by both immunophenotyping and functional criteria, indicating an obligate role for IL-15 in the development and functional maturation of NK cells. Specific defects associated with IL-15 deficiency were reversed by in vivo administration of exogenous IL-15. Despite their immunological defects, IL-15−/− mice remained healthy when maintained under specific pathogen-free conditions. However, IL-15−/− mice are likely to have compromised host defense responses to various pathogens, as they were unable to mount a protective response to challenge with vaccinia virus. These data reveal critical roles for IL-15 in the development of specific lymphoid lineages. Moreover, the ability to rescue lymphoid defects in IL-15−/− mice by IL-15 administration represents a powerful means by which to further elucidate the biological roles of this cytokine.

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15

“…Although the importance of IL-15 in this process is undisputed [19,20,[22][23][24], it is unclear whether IL-15 1) acts on early NK cell precursors, 2) is only needed at the terminal steps of NK cell development or 3) is important role in maintaining lymphocyte proliferation and homeostasis. To investigate this process, we cultured human umbilical cord blood (UCB) CD34 + Lin − CD38 − primitive progenitors on AFT024.…”

“…IRF-1 knockout mice exhibit a severe NK deficiency, which is mediated by failure of transcriptional regulation of IL-15. In addition, knockout mice deficient in IL-15 itself or IL-15Rα have very few NK cells while IL-2 and IL-2Rα knockouts are unaffected [19,20]. In human studies, IL-15 is made by stroma and macrophages [21,22].…”

Autonomous and extrinsic regulation of thymopoiesis inhuman immune system (HIS) mice

“…Indeed, mice deficient for signalling components of IL-7 and IL-15 (IL-7Ra À/À IL-2Rb À/À display a thymopoiesis block more closely resembling that of g c À/À mice than mice deficient for signalling components of IL-7 and IL-2 (IL-7Ra À/À IL-2Ra À/À ) or IL-7 and IL-4 (IL-7Ra À/À IL-4Ra À/À ) [39]. That fact that mice deficient for IL-15 or IL-15Ra display no obvious abnormalities in thymopoiesis [20,21] suggests a minor role for IL-15 in this species that is only evident when thymopoiesis is already impaired (such as in the absence of IL-7). The bioactive form of IL-15 is complexed with the IL-15Ra chain.…”

“…While IL-15 does not appear essential for thymopoiesis in mice [20,21], previous studies have shown that TEC subsets express IL-15 [22] and could ''trans-present'' IL-15/IL-15Ra complexes to developing thymocytes [23,24]. Since the bioavailability of human IL-15 in HIS mice appears limited [3], we next investigated the effect of exogenous IL-15 on human thymopoiesis in vivo.…”

Mnk kinases in cytokine signaling and regulation of cytokine responses

“…IL-15 was initially identified as a cytokine that could support the proliferation of an IL-2 dependent cell line in the presence of neutralizing antibodies against IL-2 [103,104]. Some similarities in the in vitro activities of IL-2 and IL-15 are mediated by a shared receptor subunit [105]; however studies in mice lacking IL-15 [106] or IL-2 [107] suggest that the two cytokines mediate distinct biological functions [108]. Similar to IL-2, IL-15 can mediate differentiation of NK cells as well as drive the proliferation of naïve T cells [108].…”