Cutting Edge: IL-15-Independent NK Cell Response to Mouse Cytomegalovirus Infection

Department of Microbiology and Immunology, University of California, San Francisco, CA 94143-0414, USA.
The Journal of Immunology (Impact Factor: 4.92). 07/2009; 183(5):2911-4. DOI: 10.4049/jimmunol.0901872
Source: PubMed


NK cells respond rapidly during viral infection. The development, function, and survival of NK cells are thought to be dependent on IL-15. In mice lacking IL-15, NK cells are found in severely decreased numbers. Surprisingly, following infection of IL-15- and IL-15Ralpha-deficient mice with mouse CMV, we measured a robust proliferation of Ly49H-bearing NK cells in lymphoid and nonlymphoid organs capable of cytokine secretion and cytolytic function. Remarkably, even in Rag2(-/-) x Il2rg(-/-) mice, a widely used model of NK cell deficiency, we detected a significant number of NK cells 1 wk after mouse CMV infection. In these mice we measured a >300-fold expansion of NK cells, which was dependent on recognition of the m157 viral glycoprotein ligand and IL-12. Together, these findings demonstrate a previously unrecognized independence of NK cells on IL-15 or other common gamma signaling cytokines during their response against viral infection.

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    • "IL-15 is a cytokine required for their development as shown by IL-15 KO mice, which predominantly lack NK cells [9]. Interestingly, infection of IL-15 KO mice with the protozoan parasite Toxoplasma gondii or IL-15 KO, IL-15Rα KO, and RAG2/IL-2Rγ KO mice with MCMV infection results in rapid expansion of NK cells [10, 11]. These studies support IL-15 as an important cytokine for promoting NK cell development in the absence of infection. "
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    ABSTRACT: Conventional natural killer cells (NK cells) provide continual surveillance for cancer and rapid responses to infection. They develop in the bone marrow, emerge as either NK precursor cells, immature, or mature cells, and disperse throughout the body. In the periphery NK cells provide critical defense against pathogens and cancer and are noted to develop features of adaptive immune responses. In the tightly regulated and dynamic mucosal tissues, they set up residency via unknown mechanisms and from sources that are yet to be defined. Once resident, they appear to have the ability to functionally mature dependent on the mucosal tissue microenvironment. Mucosal NK cells play a pivotal role in early protection through their cytolytic function and IFNγ production against bacteria, fungi, viruses, and parasitic infections. This review presents what is known about NK cell development and phenotypes of mucosal tissue resident conventional NK cells. The question of how they come to reside in their tissues and published data on their function against pathogens during mucosal infection are discussed. Dissecting major questions highlighted in this review will be important to the further understanding of NK cell homing and functional diversity and improve rational design of NK cell based therapies against mucosal infection.
    BioMed Research International 08/2014; 2014:413982. DOI:10.1155/2014/413982 · 3.17 Impact Factor
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    • "IL-9 induces activation of epithelial cells, B cells, eosinophils, and mast cells [13]. IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation [14], and an essential role in CD8+ T-cell homeostasis [15]. Our experiments show that in IBDV-infected chickens mRNA transcripts of 5 γc family cytokines are upregulated in bursa and inhibited in thymus, however in spleen IL-2, -7, and -9 transcripts were upregulated and the transcripts of IL-4 and -15 were inhibited, indicating that IBDV infection results in disruption of homeostasis of γc family cytokines. "
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    ABSTRACT: Infectious bursal disease virus (IBDV) infection causes immunodeficiency in chickens. To understand cell-mediated immunity during IBDV infection, this study perform a detailed analysis of chicken γc chain (chCD132) and γc family cytokines, including interleukins 2, 4, 7, 9, and 15. The mouse anti-chCD132 monoclonal antibody (mAb) was first generated by the E.coli-expressed γc protein. Immunofluorescence assay further showed that γc was a protein located with the anti-chCD132 mAb on the surface of chicken's splenic mononuclear cells. Real-time quantitative RT-PCR revealed that the chCD132 mRNA transcript was persistently downregulated in embryo fibroblasts, spleen and thymus of chickens infected with IBDV. Correspondingly during IBDV infection, the transcription of five γc family cytokines was downregulated in the thymus and presented an imbalance in the spleen. Fluorescence-activated cell sorting analyses also indicated that the percentage of CD132(+)CD8(+) T cells linearly decreased in the bursa of IBDV-infected chickens. These results confirmed that IBDV infection disturbed the in vivo balance of CD132 and γc family cytokine expression and that IBDV-induced immunodeficiency involved cellular networks related to the γc family.
    PLoS ONE 01/2014; 9(1):e84503. DOI:10.1371/journal.pone.0084503 · 3.23 Impact Factor
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    • "More recently, it has been shown that IL-12 in combination with another cytokine, IL-18, helps optimal NK cell expansion (125, 126) an effect which is not dependent on IFN-γ secretion. Moreover, in some settings, IL-12/IL-18 can drive an IL-15 independent response of NK cells (127, 128). However these results are controversial, indeed, another study found no or only a very minor role of IL-18 and IL-12 for the promotion of the expansion of Ly49H+ NK cells during MCMV infection in vivo (129). "
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    ABSTRACT: Natural Killer (NK) cells are innate lymphocytes with an important role in the early defense against intracellular pathogens and against tumors. Like other immune cells, almost every aspects of their biology are regulated by cytokines. Interleukin (IL)-15 is pivotal for their development, homeostasis, and activation. Moreover, numerous other activating or inhibitory cytokines such as IL-2, IL-4, IL-7, IL-10, IL-12, IL-18, IL-21, Transforming growth factor-β (TGFβ) and type I interferons regulate their activation and their effector functions at different stages of the immune response. In this review we summarize the current understanding on the effect of these different cytokines on NK cell development, homeostasis, and functions during steady-state or upon infection by different pathogens. We try to delineate the cellular sources of these cytokines, the intracellular pathways they trigger and the transcription factors they regulate. We describe the known synergies or antagonisms between different cytokines and highlight outstanding questions in this field of investigation. Finally, we discuss how a better knowledge of cytokine action on NK cells could help improve strategies to manipulate NK cells in different clinical situations.
    Frontiers in Immunology 12/2013; 4:450. DOI:10.3389/fimmu.2013.00450
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