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ABSTRACT: The emergence of the adaptive immune system took a toll in the form of pathologies mediated by self-reactive cells. Regulatory T cells (T reg cells) exert a critical brake on responses of T and B lymphocytes to self- and foreign antigens. Here, we asked whether T reg cells are required to restrain NK cells, the third lymphocyte lineage, whose features combine innate and adaptive immune cell properties. Although depletion of T reg cells led to systemic fatal autoimmunity, NK cell tolerance and reactivity to strong activating self- and non-self-ligands remained largely intact. In contrast, missing-self responses were increased in the absence of T reg cells as the result of heightened IL-2 availability. We found that IL-2 rapidly boosted the capacity of NK cells to productively engage target cells and enabled NK cell responses to weak stimulation. Our results suggest that IL-2-dependent adaptive-innate lymphocyte cross talk tunes NK cell reactivity and that T reg cells restrain NK cell cytotoxicity by limiting the availability of IL-2.
Journal of Experimental Medicine 05/2013; · 13.85 Impact Factor
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ABSTRACT: Activation and expansion of T and B lymphocytes and myeloid cells are controlled by Foxp3(+) regulatory T cells (T reg cells), and their deficiency results in a fatal lympho- and myeloproliferative syndrome. A role for T reg cells in the homeostasis of innate lymphocyte lineages remained unknown. Here, we report that T reg cells restrained the expansion of immature CD127(+) NK cells, which had the unique ability to up-regulate the IL2Rα (CD25) in response to the proinflammatory cytokine IL-12. In addition, we observed the preferential accumulation of CD127(+) NK cells in mice bearing progressing tumors or suffering from chronic viral infection. CD127(+) NK cells expanded in an IL-2-dependent manner upon T reg cell depletion and were able to give rise to mature NK cells, indicating that the latter can develop through a CD25(+) intermediate stage. Thus, T reg cells restrain the IL-2-dependent CD4(+) T cell help for CD127(+) immature NK cells. These findings highlight the adaptive control of innate lymphocyte homeostasis.
Journal of Experimental Medicine 05/2013; · 13.85 Impact Factor
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ABSTRACT: The important role of microRNAs in directing immune responses has become increasingly clear. Here, we highlight discoveries uncovering the role of specific microRNAs in regulating the development and function of natural killer (NK) cells. Furthermore, we discuss the impact of NK cells on the entire immune system during global and specific microRNA ablation in the settings of inflammation, infection, and immune dysregulation.
Immunological Reviews 05/2013; 253(1):40-52. · 11.15 Impact Factor
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ABSTRACT: Natural killer (NK) cells function in the recognition and destruction of host cells infected with pathogens. Many regulatory mechanisms govern the potent responses of NK cells, both at the cellular and molecular level. Ablation of microRNA (miRNA) processing enzymes demonstrated that miRNAs play critical roles in NK cell differentiation and function; however, the role of individual miRNAs requires further investigation. Using mice containing a targeted deletion of microRNA-155 (miR-155), we observed defects in NK cell maintenance and maturation at steady state, as well as in homeostatic proliferation in lymphopenic mice. In addition, we discovered that miR-155 is up-regulated in activated NK cells during mouse cytomegalovirus (MCMV) infection in response to signals from the proinflammatory cytokines IL-12 and IL-18 and through signal transducer and activator of transcription 4 (STAT4) signaling. Although miR-155 was found to be dispensable for cytotoxicity and cytokine production when triggered through activating receptors, NK cells lacking miR-155 exhibited severely impaired effector and memory cell numbers in both lymphoid and nonlymphoid tissues after MCMV infection. We demonstrate that miR-155 differentially targets Noxa and suppressor of cytokine signaling 1 (SOCS1) in NK cells at distinct stages of homeostasis and activation. NK cells constitutively expressing Noxa and SOCS1 exhibit profound defects in expansion during the response to MCMV infection, suggesting that their regulation by miR-155 promotes antiviral immunity.
Proceedings of the National Academy of Sciences 04/2013; · 9.68 Impact Factor
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ABSTRACT: Although natural killer (NK) cells are classified as innate immune cells, recent studies demonstrate that NK cells can become long-lived memory cells and contribute to secondary immune responses. The precise signals that promote generation of long-lived memory NK cells are unknown. Using cytokine receptor-deficient mice, we show that interleukin-12 (IL-12) is indispensible for mouse cytomegalovirus (MCMV)-specific NK cell expansion and generation of memory NK cells. In contrast to wild-type NK cells that proliferated robustly and resided in lymphoid and nonlymphoid tissues for months after MCMV infection, IL-12 receptor-deficient NK cells failed to expand and were unable to mediate protection after MCMV challenge. We further demonstrate that a STAT4-dependent IFN-γ-independent mechanism contributes toward the generation of memory NK cells during MCMV infection. Understanding the full contribution of inflammatory cytokine signaling to the NK cell response against viral infection will be of interest for the development of vaccines and therapeutics.
Journal of Experimental Medicine 04/2012; 209(5):947-54. · 13.85 Impact Factor
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ABSTRACT: Natural killer (NK) cells survey host tissues for signs of infection, transformation or stress and, true to their name, kill target cells that have become useless or are detrimental to the host. For decades, NK cells have been classified as a component of the innate immune system. However, accumulating evidence in mice and humans suggests that, like the B and T cells of the adaptive immune system, NK cells are educated during development, possess antigen-specific receptors, undergo clonal expansion during infection and generate long-lived memory cells. In this Review, we highlight the many stages that an NK cell progresses through during its remarkable lifetime, discussing similarities and differences with its close relative, the cytotoxic CD8(+) T cell.
Nature Reviews Immunology 08/2011; 11(10):645-57. · 32.25 Impact Factor
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ABSTRACT: NK cells recognize virus-infected cells with germline-encoded activating and inhibitory receptors that do not undergo genetic recombination or mutation. Accordingly, NK cells are often considered part of the innate immune response. The innate response comprises rapid early defenders that do not form immune memory. However, there is increasing evidence that experienced NK cells provide increased protection to secondary infection, a hallmark of the adaptive response. In this study, we compare the dynamics of the innate and adaptive immune responses by examining the kinetic profiles of the NK and T cell response to murine CMV infection. We find that, unexpectedly, the kinetics of NK cell proliferation is neither earlier nor faster than the CD4 or CD8 T cell response. Furthermore, early NK cell contraction after the peak of the response is slower than that of T cells. Finally, unlike T cells, experienced NK cells do not experience biphasic decay after the response peak, a trait associated with memory formation. Rather, NK cell contraction is continuous, constant, and returns to below endogenous preinfection levels. This indicates that the reason why Ag-experienced NK cells remain detectable for a prolonged period after adoptive transfer and infection is in part due to the high precursor frequency, slow decay rate, and low background levels of Ly49H(+) NK cells in recipient DAP12-deficient mice. Thus, the quantitative contribution of Ag-experienced NK cells in an endogenous secondary response, with higher background levels of Ly49H(+) NK cells, may be not be as robust as the secondary response observed in T cells.
The Journal of Immunology 06/2011; 187(3):1385-92. · 5.79 Impact Factor
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ABSTRACT: Immunological memory is a hallmark of the adaptive immune system. However, the ability to remember and respond more robustly against a second encounter with the same pathogen has been described in organisms lacking T and B cells. Recently, NK cells have been shown to mediate Ag-specific recall responses in several different model systems. Although NK cells do not rearrange the genes encoding their activating receptors, NK cells experience a selective education process during development, undergo a clonal-like expansion during virus infection, generate long-lived progeny (i.e., memory cells), and mediate more efficacious secondary responses against previously encountered pathogens--all characteristics previously ascribed only to T and B cells in mammals. This review describes past findings leading up to these new discoveries, summarizes the evidence for and characteristics of NK cell memory, and discusses the attempts and future challenges to identify these long-lived memory NK cell populations in humans.
The Journal of Immunology 02/2011; 186(4):1891-7. · 5.79 Impact Factor
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ABSTRACT: Cells of the immune system undergo homeostatic proliferation during times of lymphopenia induced by certain viral infections or caused by chemotherapy and radiation treatment. Natural killer (NK) cells are no exception and can rapidly expand in number when placed into an environment devoid of these cells. We explored the lifespan and function of mouse NK cells that have undergone homeostatic proliferation in various settings of immunodeficiency. Adoptive transfer of mature NK cells into lymphopenic mice resulted in the generation of a long-lived population of NK cells. These homeostasis-driven NK cells reside in both lymphoid and nonlymphoid organs for >6 mo and, similar to memory T cells, self-renew and slowly turn over at steady state. Furthermore, homeostatically expanded NK cells retained their functionality many months after initial transfer and responded robustly to viral infection. These findings highlight the ability of mature NK cells to self-renew and possibly persist in the host for months or years and might be of clinical importance during NK cell adoptive immunotherapy for the treatment of certain cancers.
Journal of Experimental Medicine 02/2011; 208(2):357-68. · 13.85 Impact Factor
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ABSTRACT: The protein tyrosine phosphatase CD45 is an important regulator of Src-family kinase activity. We found that in the absence of CD45, natural killer (NK) cells are defective in protecting the host from mouse cytomegalovirus infection. We show that although CD45 is necessary for all immunoreceptor tyrosine-based activation motif (ITAM)-specific NK-cell functions and processes such as degranulation, cytokine production, and expansion during viral infection, the impact of CD45 deficiency on ITAM signaling differs depending on the downstream function. CD45-deficient NK cells are normal in their response to inflammatory cytokines when administered ex vivo and in the context of viral infection. Syk and ζ chain-associated protein kinase 70 (Zap70) are thought to play redundant roles in transmitting ITAM signals in NK cells. We show that Syk, but not Zap70, controls the remaining CD45-independent, ITAM-specific NK-cell functions, demonstrating a functional difference between these 2 Syk-kinase family members in primary NK cells.
Blood 01/2011; 117(11):3087-95. · 9.90 Impact Factor
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Immunology and Cell Biology 12/2010; 89(3):327-9. · 3.66 Impact Factor
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Joseph C Sun
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ABSTRACT: The development and function of natural killer (NK) cells is dictated by signals received through activating and inhibitory receptors expressed on the cell surface. During their maturation in the bone marrow, NK cells undergo an education process that ensures they are tolerant to healthy peripheral tissues. Several recent studies advance our understanding of self-tolerance mechanisms at work in NK cells. These studies demonstrate that the developmental programming in NK cells is not fixed, and that perturbations to the peripheral environment (via transplantation or viral infection, for example) greatly influence the ability of mature NK cells to mount an effector response. This newfound ability of mature NK cells to be "re-educated" may be clinically applicable in the immunotherapeutic use of NK cells against infection and cancer.
Journal of Experimental Medicine 09/2010; 207(10):2049-52. · 13.85 Impact Factor
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ABSTRACT: Natural killer (NK) cells respond rapidly to transformed, stressed, or virally infected cells and provide a first-line immune defense against pathogen invasion and cancer. Thought to involve short-lived effector cells that are armed for battle, NK cells were not previously known to contribute in recall responses to pathogen re-encounter. Here, we highlight recent discoveries demonstrating that NK cells are not limited to driving primary immune responses to foreign antigen but can mount secondary responses contributing to immune memory. We also further characterize the phenotype and function of long-lived memory NK cells generated during viral infection.
Immunological Reviews 07/2010; 236:83-94. · 11.15 Impact Factor
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ABSTRACT: Since their discovery three decades ago, NK cells have been classified as cells of the innate immune system. NK cells were shown to respond rapidly and non-specifically to infection, and were thought to act as a functional "bridge" to sustain the early innate immune response until the later adaptive immune responses could be mounted. In light of new findings showing how NK cells possess nearly all of the features of adaptive immunity including memory, we propose the placement of NK cells as an "evolutionary bridge" between innate and adaptive immunity.
European Journal of Immunology 08/2009; 39(8):2059-64. · 5.10 Impact Factor
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ABSTRACT: 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.
The Journal of Immunology 07/2009; 183(5):2911-4. · 5.79 Impact Factor
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Nature Reviews Immunology 06/2009; 9(5):302-3. · 32.25 Impact Factor
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ABSTRACT: The activating natural killer (NK) cell receptor Ly49H recognizes the mouse cytomegalovirus (MCMV) m157 glycoprotein expressed on the surface of infected cells and is required for protection against MCMV. Although Ly49H has previously been shown to signal via DAP12, we now show that Ly49H must also associate with and signal via DAP10 for optimal function. In the absence of DAP12, DAP10 enables Ly49H-mediated killing of m157-bearing target cells, proliferation in response to MCMV infection, and partial protection against MCMV. DAP10-deficient Ly49H(+) NK cells, expressing only Ly49H-DAP12 receptor complexes, are partially impaired in their ability to proliferate during MCMV infection, display diminished ERK1/2 activation, produce less IFN-gamma upon Ly49H engagement, and demonstrate reduced control of MCMV infection. Deletion of both DAP10 and DAP12 completely abrogates Ly49H surface expression and control of MCMV infection. Thus, optimal NK cell-mediated immunity to MCMV depends on Ly49H signaling through both DAP10 and DAP12.
Journal of Experimental Medicine 04/2009; 206(4):807-17. · 13.85 Impact Factor
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ABSTRACT: In an adaptive immune response, naive T cells proliferate during infection and generate long-lived memory cells that undergo secondary expansion after a repeat encounter with the same pathogen. Although natural killer (NK) cells have traditionally been classified as cells of the innate immune system, they share many similarities with cytotoxic T lymphocytes. We use a mouse model of cytomegalovirus infection to show that, like T cells, NK cells bearing the virus-specific Ly49H receptor proliferate 100-fold in the spleen and 1,000-fold in the liver after infection. After a contraction phase, Ly49H-positive NK cells reside in lymphoid and non-lymphoid organs for several months. These self-renewing 'memory' NK cells rapidly degranulate and produce cytokines on reactivation. Adoptive transfer of these NK cells into naive animals followed by viral challenge results in a robust secondary expansion and protective immunity. These findings reveal properties of NK cells that were previously attributed only to cells of the adaptive immune system.
Nature 02/2009; 457(7229):557-61. · 36.28 Impact Factor
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ABSTRACT: NK cells attack cells lacking MHC class I, yet MHC class I-deficient mice have normal numbers of NK cells with intact, albeit diminished, functions. Moreover, wild-type NK cells are tolerant of MHC class I-deficient cells in mixed bone marrow chimeras. In this study, we investigated how the absence of MHC class I affects NK cells. NK cells from beta(2)-microglobulin-deficient (B2m(-/-)) and wild-type mice exhibit similar phenotypic and functional characteristics. Both B2m(-/-) and wild-type Ly49H(+) NK cells proliferated robustly and produced IFN-gamma after infection with mouse CMV. NK cells in mixed wild-type:B2m(-/-) chimeric mice were initially tolerant of MHC class I-deficient host cells. However, this tolerance was gradually lost over time and after mouse CMV infection was rapidly broken, with a pronounced rejection of host B2m(-/-) hematopoietic cells. Thus, although NK cells can be held in check against "missing self," acute inflammation driven by infection can rapidly break established self-tolerance.
The Journal of Immunology 01/2009; 181(11):7453-7. · 5.79 Impact Factor
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ABSTRACT: During the co-evolution of cytomegalovirus (CMV) and natural killer (NK) cells, each has evolved specific tactics in an attempt to prevail. CMV has evolved multiple immune evasion mechanisms to avoid detection by NK cells and other immune cells, leading to chronic infection. Meanwhile, the host has evolved virus-specific receptors to counter these evasion strategies. The natural selection of viral genes and host receptors allows us to observe a unique molecular example of "survival of the fittest", as virus and immune cells try to out-maneuver one another or for the virus to achieve détente for optimal dissemination in the population.
Viruses 01/2009; 1(3):362. · 1.50 Impact Factor
