IL-2, IL-15, and IL-7 are cytokines that are critical for regulating lymphoid homeostasis. These cytokines stimulate similar responses from lymphocytes in vitro, but play markedly divergent roles in lymphoid biology in vivo. Their distinct physiological functions can be ascribed to distinct signaling pathways initiated by proprietary cytokine receptor chains, differential expression patterns of the cytokines or their receptor chains, and/or signals occurring in distinct physiological contexts. Recently, the discovery of a novel mechanism of cytokine signaling, trans-presentation, has provided further insights into the different ways these cytokines function. Trans-presentation also raises several novel cell biological and cellular implications concerning how cytokines support lymphoid homeostasis.

The high affinity interleukin (IL)-15 receptor, IL-15Rα, is essential for supporting lymphoid homeostasis. To assess whether IL-15Rα's role in vivo is to trans present IL-15, we generated mixed bone marrow chimera from IL-15Rα– and IL-2/15Rβ–deficient mice. We find that IL-15Rα–competent, IL-2/15Rβ–deficient cells are able to support IL-15Rα–deficient natural killer (NK) and memory CD8+ T cells, thus ruling out secondary signals on these cells and demonstrating that IL-15Rα–mediated presentation of IL-15 in trans is the primary mechanism by which IL-15Rα functions in vivo. Surprisingly, using IL-15– and IL-15Rα–deficient mixed chimera, we also find that IL-15 and IL-15Rα must be expressed by the same cells to present IL-15 in trans, indicating that IL-15Rα is required on a cellular level for the elaboration of IL-15. These studies indicate that IL-15Rα defines homeostatic niches for NK and memory CD8+ T cells by controlling both the production and the presentation of IL-15 in trans to NK and CD8+ memory T cells.

Natural killer (NK) cells protect hosts against viral pathogens and transformed cells. IL-15 is thought to play a critical role in NK cell development, but its role in the regulation of peripheral NK cells is less well defined. We now find that adoptive transfer of normal NK cells into mice lacking the high affinity interleukin (IL)-15 receptor, IL-15Rα, surprisingly results in the abrupt loss of these cells. Moreover, IL-15Rα–deficient NK cells can differentiate successfully in radiation bone marrow chimera bearing normal cells. Finally, adoptively transferred IL-15Rα–deficient NK cells survive in normal but not IL-15Rα–deficient mice. These findings demonstrate that NK cell–independent IL-15Rα expression is critical for maintaining peripheral NK cells, while IL-15Rα expression on NK cells is not required for this function.

The generation and maintenance of immunological memory requires the activation, expansion, and persistent proliferation of antigen-specific T cells. Recent work suggests that IL-15 may be important for this process. Surprisingly, we now find that expression of the high-affinity receptor for IL-15, IL-15R␣, on T cells is dispensable for the generation or maintenance of memory CD8 ؉ T cells. By contrast, IL-15R␣ expression on cells other than T cells is absolutely critical for this function. These findings may be related to IL-15R␣'s ability to present IL-15 in trans to low-affinity IL15R␤͞␥c receptors on memory CD8 ؉ T cells. These unexpected results provide insights into how IL-15R␣ supports memory CD8 ؉ T cells.M emory CD8 ϩ T cells are critical mediators of immunity to intracellular pathogens. The signals that support homeostasis of memory CD8 ϩ T cells have only recently begun to be elucidated. Unlike their naïve counterparts, memory CD8 ϩ T cells do not require interaction with cognate MHC (1). Rather, cytokines that use the common ␥ (␥ c ) chain for receptor signaling appear to play a central role in the support of memory CD8 ϩ T cells. Two such cytokines, IL-7 and IL-15, have been shown to regulate memory CD8 ϩ T cell homeostasis. However, whereas IL-7 primarily supports proliferation of both naïve and memory CD8 ϩ T cells in lymphopenic states, IL-15 specifically regulates the survival and proliferation of memory CD8 ϩ T cells under normal physiological conditions. IL-15 is a four-␣-helix bundle family cytokine both functionally and structurally similar to IL-2 (2, 3). The heterotrimeric IL-15 receptor (IL-15R) consists of IL-15R␣, which uniquely binds IL-15, as well as IL-2R␤ and ␥ c (4, 5). IL-15R␣ alone binds IL-15 with a K d of Ϸ1 ϫ 10 Ϫ11 M. Consistent with IL-15's functional homology to IL-2, IL-15R shares IL-2R␤ and ␥ c subunits with IL-2R, and these subunits mediate signaltransduction events after IL-2 or IL-15 binding. Whereas IL-2R␤ and ␥ c are able to bind IL-15 without IL-15R␣, the similar phenotypes of IL-15 Ϫ/Ϫ and IL-15R␣ Ϫ/Ϫ mice suggest that IL-15R␣ is required for IL-15 signals in vivo.Several lines of evidence suggest that IL-15 selectively supports the survival and proliferation of both memory and memory phenotype (CD44 Hi IL-2R␤ Hi ) CD8 ϩ T cells. First, memory phenotype cells express high levels of IL-2R␤, a key component of the IL-15R complex, and in vivo administration of anti-IL-2R␤-specific, but not anti-IL-2R␣-specific, antibodies blocks the basal proliferation of these cells (6). Second, administration of recombinant IL-15 selectively stimulates the proliferation of memory phenotype CD8 ϩ T cells both in vivo and in vitro (7). Third, both IL-15 Ϫ/Ϫ and IL-15R␣ Ϫ/Ϫ mice have severely reduced numbers of memory phenotype cells, whereas mice that overexpress a readily secreted form of IL-15 possess increased numbers of these cells (8-10). Finally, recent studies using IL-15 Ϫ/Ϫ or IL-15R␣ Ϫ/Ϫ mice suggest that antigen-experienced CD8 ϩ memory T cells require both IL-15 and IL-15R␣...

NK cells protect hosts against viral pathogens and transformed cells, and dendritic cells (DCs) play important roles in activating NK cells. We now find that murine IL-15Rα-deficient DCs fail to support NK cell cytolytic activity and elaboration of IFN-γ, despite the fact that these DCs express normal levels of costimulatory molecules and IL-12. By contrast, IL-15Rα expression on NK cells is entirely dispensable for their activation by DCs. In addition, blockade with anti-IL-15Rα and anti-IL-2Rβ but not anti-IL-2Rα-specific Abs prevents NK cell activation by wild-type DCs. Finally, presentation of IL-15 by purified IL-15Rα/Fc in trans synergizes with IL-12 to support NK cell priming. These findings suggest that murine DCs require IL-15Rα to present IL-15 in trans to NK cells during NK cell priming.

Background Sub-Saharan Africa and south Asia contributed 81% of 5•9 million under-5 deaths and 77% of 2•6 million stillbirths worldwide in 2015. Vital registration and verbal autopsy data are mainstays for the estimation of leading causes of death, but both are non-specific and focus on a single underlying cause. We aimed to provide granular data on the contributory causes of death in stillborn fetuses and in deceased neonates and children younger than 5 years, to inform child mortality prevention efforts. Methods The Child Health and Mortality Prevention Surveillance (CHAMPS) Network was established at sites in seven countries (

Humans and mice deficient in Fas, a tumor necrosis factor (TNF)-receptor family member, cannot induce apoptosis of autoreactive cells, and consequently develop progressive lymphoproliferative disorders and lupus-like autoimmune diseases. Previous studies have shown that short-term administrations of agonistic monoclonal antibodies against CD137, another TNF-receptor family member, activate T cells and induce rejection of allografts and established tumors. Here we report that treatment with an agonistic monoclonal antibody to CD137 (2A) blocks lymphadenopathy and spontaneous autoimmune diseases in Fas-deficient MRL/lpr mice, ultimately leading to their prolonged survival. Notably, 2A treatment rapidly augments IFN-gamma production, and induces the depletion of autoreactive B cells and abnormal double-negative T cells, possibly by increasing their apoptosis through Fas- and TNF receptor-independent mechanisms. This study demonstrates that agonistic monoclonal antibodies specific for costimulatory molecules can be used as novel therapeutic agents to delete autoreactive lymphocytes and block autoimmune disease progression.

NK cells vigorously proliferate during viral infections. During the course of murine CMV infection, this response becomes dominated by the preferential proliferation of NK cells that express the activation receptor Ly49H. The factors driving such selective NK cell proliferation have not been characterized. In this study, we demonstrate that preferential NK cell proliferation is dependent on DAP12-mediated signaling following the binding of Ly49H to its virally encoded ligand, m157. Ly49H signaling through DAP12 appears to directly augment NK cell sensitivity to low concentrations of proproliferative cytokines such as IL-15. The impact of Ly49H-mediated signaling on NK cell proliferation is masked in the presence of high concentrations of proproliferative cytokines that nonselectively drive all NK cells to proliferate.