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ABSTRACT: The maternal immune response during pregnancy is critical for the survival of the fetus yet can be detrimental during infection and inflammation. Previously, IL-15 has been observed to mediate inflammation during LPS-induced sepsis. Therefore, we sought to determine whether IL-15 mediates the inflammatory process during LPS-induced abortion through the use of IL-15(-/-) and WT mice. Administration of 2.5 μg LPS i.p. on gd 7.5 drastically reduced fetal viability in WT mice, whereas it had a minimal effect on fetal survival in IL-15(-/-) mice. The uteroplacental sites of LPS-treated WT mice were characterized by vast structural degradation and inflammation compared with treated IL-15(-/-) and untreated controls. This suggests that IL-15 may mediate the inflammation responsible for LPS-induced resorption. As IL-15(-/-) mice are deficient in NK cells and resistant to LPS-induced abortion, these effects suggest that IL-15 may mediate abortion through their homeostatic and/or activation effects on NK cells. WT uteroplacental units exposed to LPS had an increase in the overall number and effector number of NK cells compared with their control counterparts. Furthermore, NK cell depletion before administration of LPS in WT mice partially restored fetal viability. Overall, this paper suggests that IL-15 mediates the inflammatory environment during LPS-induced fetal resorption, primarily through its effects on NK cells.
Journal of leukocyte biology 03/2013; · 4.99 Impact Factor
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ABSTRACT: Numerous reviews in the field of NK cell biology dictate the pivotal role that NK cells play in tumor rejection. Although these cell types were originally described based on their cytotoxic ability, we now know that NK cells are not naturally born to kill. Both cellular interactions and the local environment in which the NK cell resides in may influence its cytotoxic functions. Just as organ specific NK cells have distinct phenotypic and functional differences, the tumor is a unique microenvironment in itself. The NK cells originally recruited to the tumor site are able to stimulate immune responses and aid in tumor destruction but eventually become persuaded otherwise by mechanisms of immunosuppression. Here, we review potential mechanisms and players involved in NK cell immunosuppression. In particular the effects of another innate immune player, macrophages, will be addressed in augmenting immunosuppression of NK cells within tumors. Tumor-associated macrophages (TAMs) are the main regulatory population of myeloid cells in the tumor and are characterized by their ability to promote tumor cell proliferation and metastasis. In addition, they express/release immunoregulatory factors which have been shown to directly inhibit NK cell function. Understanding how these two cell types interact in the distinct tumor microenvironment will allow us to consider therapies that target TAMs to promote enhanced NK cell activity.
Current Molecular Medicine 07/2012; · 5.10 Impact Factor
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Mohamed F Abdul-Careem,
M Firoz Mian,
Geoffry Yue,
Amy Gillgrass,
Meghan J Chenoweth,
Nicole G Barra,
Marianne V Chew,
Tiffany Chan,
Amal A Al-Garawi,
Manel Jordana, Ali A Ashkar
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ABSTRACT: Influenza viral infection results in excessive pulmonary inflammation that has been linked to the damage caused by immune responses and viral replication. The multifunctional cytokine interleukin (IL-15), influences the proliferation and maintenance of immune cells such as CD8(+) T cells and natural killer (NK) cells. Here we show that IL-15(-/-) mice are protected from lethal influenza infection. Irrespective of the mouse strains, the protection observed was linked to the lack of NK cells. Increased survival in the IL-15(-/-) or NK1.1(+) cell-depleted wild-type mice was associated with significantly lower lung lesions as well as decreased mononuclear cells and neutrophils in the airway lumen. Levels of interleukin 10 were significantly higher and levels of proinflammatory cytokines, including interleukin 6 and interleukin 12, were significantly lower in the bronchoalveolar lavage fluid from IL-15(-/-) and NK1.1(+) cell-depleted wild-type mice than in that from control mice. Our data suggest that NK cells significantly augment pulmonary inflammation, contributing to the pathogenesis of influenza infection.
The Journal of Infectious Diseases 05/2012; 206(2):167-77. · 6.41 Impact Factor
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ABSTRACT: IL-15 plays many important roles within the immune system. IL-15 signals in lymphocytes via trans presentation, where accessory cells such as macrophages and dendritic cells present IL-15 bound to IL-15Rα in trans to NK cells and CD8(+) memory T cells expressing IL-15/IL-2Rβ and common γ chain (γ(c)). Previously, we showed that the prophylactic delivery of IL-15 to Rag2(-/-)γ(c)(-/-) mice (mature T, B, and NK cell negative) afforded protection against a lethal HSV-2 challenge and metastasis of B16/F10 melanoma cells. In this study, we demonstrated that in vivo delivery of an adenoviral construct optimized for the secretion of human IL-15 to Rag2(-/-)γ(c)(-/-) mice resulted in significant increases in spleen size and cell number, leading us to hypothesize that IL-15 signals differently in myeloid immune cells compared with lymphocytes, for which IL-15/IL-2Rβ and γ(c) expression are essential. Furthermore, treatment with IL-15 induced RANTES production by Rag2(-/-)γ(c)(-/-) bone marrow cells, but the presence of γ(c) did not increase bone marrow cell sensitivity to IL-15. This IL-15-mediated RANTES production by Rag2(-/-)γ(c)(-/-) bone marrow cells occurred independently of the IL-15/IL-2Rβ and Jak/STAT pathways and instead required IL-15Rα signaling as well as activation of JNK and NF-κB. Importantly, we also showed that the trans presentation of IL-15 by IL-15Rα boosts IL-15-mediated IFN-γ production by NK cells but reduces IL-15-mediated RANTES production by Rag2(-/-)γ(c)(-/-) myeloid bone marrow cells. Our data clearly show that IL-15 signaling in NK cells is different from that of myeloid immune cells. Additional insights into IL-15 biology may lead to novel therapies aimed at bolstering targeted immune responses against cancer and infectious disease.
The Journal of Immunology 03/2012; 188(9):4149-57. · 5.79 Impact Factor
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ABSTRACT: NK cells are known as innate immune cells that lack immunological memory. Recently, it has been shown that NK cells remember encounters with chemical haptens that induce contact hypersensitivity and cytomegalovirus infection. Here, we show the existence of NK cell memory following HSV-2 infection. Stimulation with HSV-2 Ags led to higher IFNγ production in NK cells that were exposed 30 days previously to HSV-2, compared to NK cells from naïve mice. More importantly, this increased production of IFNγ in NK cells was independent of B- and T- lymphocytes and specific for the HSV-2 Ags. We also showed that previously exposed NK cells in a B- and T-lymphocyte free environment mediate protection against HSV-2 infection and they are necessary for the protection of mice against HSV-2 infection. Collectively, NK cells remember prior HSV-2 encounters independent of B- and T- lymphocytes leading to protection against HSV-2 mediated morbidity and mortality upon re-exposure.
PLoS ONE 01/2012; 7(3):e32821. · 4.09 Impact Factor
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ABSTRACT: The innate host response to virus infection is largely dominated by the production of type I interferon and interferon stimulated genes. In particular, fibroblasts respond robustly to viral infection and to recognition of viral signatures such as dsRNA with the rapid production of type I interferon; subsequently, fibroblasts are a key cell type in antiviral protection. We recently found, however, that primary fibroblasts deficient for the production of interferon, interferon stimulated genes, and other cytokines and chemokines mount a robust antiviral response against both DNA and RNA viruses following stimulation with dsRNA. Nitric oxide is a chemical compound with pleiotropic functions; its production by phagocytes in response to interferon-γ is associated with antimicrobial activity. Here we show that in response to dsRNA, nitric oxide is rapidly produced in primary fibroblasts. In the presence of an intact interferon system, nitric oxide plays a minor but significant role in antiviral protection. However, in the absence of an interferon system, nitric oxide is critical for the protection against DNA viruses. In primary fibroblasts, NF-κB and interferon regulatory factor 1 participate in the induction of inducible nitric oxide synthase expression, which subsequently produces nitric oxide. As large DNA viruses encode multiple and diverse immune modulators to disable the interferon system, it appears that the nitric oxide pathway serves as a secondary strategy to protect the host against viral infection in key cell types, such as fibroblasts, that largely rely on the type I interferon system for antiviral protection.
PLoS ONE 01/2012; 7(2):e31688. · 4.09 Impact Factor
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ABSTRACT: Obesity is a chronic inflammatory condition characterized by activation and infiltration of proinflammatory immune cells and a dysregulated production of proinflammatory cytokines. While known as a key regulator of immune natural killer (NK) cell function and development, we have recently demonstrated that reduced expression of the cytokine Interleukin-15 (IL-15) is closely linked with increased body weight and adiposity in mice and humans. Previously, we and others have shown that obese individuals have lower circulating levels of IL-15 and NK cells. Lean IL-15 overexpressing (IL-15 tg) mice had an accumulation in adipose NK cells compared to wildtype and NK cell deficient obese IL-15(-/-) mice. Since IL-15 induces weight loss in IL-15(-/-) and diet induced obese mice and has effects on various lymphocytes, the aim of this paper was to determine if lymphocytes, particularly NK cells, play a role in IL-15 mediated weight loss. Acute IL-15 treatment resulted in an increased accumulation of NK, NKT, and CD3(+) T cells in adipose tissue of B6 mice. Mice depleted of NK and NKT cells had similar weight loss comparable to controls treated with IL-15. Finally, IL-15 treatment induces significant weight loss in lymphocyte deficient RAG2(-/-)γc(-/-) mice independent of food intake. Fat pad cross-sections show decreased pad size with cytokine treatment is due to adipocyte shrinkage. These results clearly suggest that IL-15 mediates weight loss independent of lymphocytes.
PLoS ONE 01/2012; 7(6):e39553. · 4.09 Impact Factor
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ABSTRACT: Herpes simplex virus (HSV)-2 is the predominant cause of genital herpes and has been implicated in HIV infection and transmission. Thus far, vaccines developed against HSV-2 have been clinically ineffective in preventing infection. This review aims to summarize the innate and adaptive immune responses against HSV-2 and examines the current status of vaccine development.
Both innate and adaptive immune responses are essential for an effective primary immune response and the generation of immunity. The innate response involves Toll-like receptors, natural killer cells, plasmacytoid dendritic cells, and type I, II, and III interferons. The adaptive response requires a balance between CD4+ and CD8+ T-cells for optimal viral clearance. T-regulatory cells may be involved, although their exact function has yet to be determined. Current vaccine development involves the use of HSV-2 peptides or attenuated/replication-defective HSV-2 to generate adaptive anti-HSV-2 immune responses, however the generation of innate responses may also be an important consideration.
Although vaccine development has primarily focused on the adaptive response, arguments for innate involvement are emerging. A greater understanding of the innate and adaptive processes underlying the response to HSV-2 infection will provide the foundation for the development of an effective vaccine.
Current Opinion in Infectious Diseases 12/2011; 25(1):92-9. · 4.93 Impact Factor
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Mohamed F Abdul-Careem,
M Firoz Mian,
Amy E Gillgrass,
Meghan J Chenoweth,
Nicole G Barra,
Tiffany Chan,
Amal A Al-Garawi,
Marianne V Chew,
Geoffry Yue,
Nico van Roojen,
Zhou Xing, Ali A Ashkar
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ABSTRACT: Fimbriae H protein (FimH) is a novel TLR4 ligand that has been shown to stimulate the innate immune system and elicits protective responses against bacterial and viral infections. Here, we evaluated the protective role of local delivery of FimH against influenza A infection in a mouse model. We show that intranasal delivery of FimH prior to lethal challenge with influenza A virus, resulted in decreased morbidity and mortality in wild-type, but not TLR4(-/-), mice. Importantly, FimH was able to reduce the early viral burden in the lung leading to minimal cell infiltration into the airway lumen and reduced pulmonary pathology following infection in wild type mice compared to TLR4(-/-) mice. Local delivery of FimH to C57BL/6, not TLR4(-/-), mice in a prophylactic manner increased the IL-12 and RANTES responses as well as neutrophil recruitment into the airway lumen. These effects correlate to the course of influenza infection. The FimH-mediated antiviral response against influenza virus appears to be partially dependent on alveolar macrophages. The antiviral effects are likely mediated by the innate mediators (TNF-α, IL-12 or RANTES) and/or by activation of a feedback inhibition loop to curtail the pulmonary inflammation possibly be the potential mechanisms involved in FimH-mediated protection. FimH thus holds promise to be a possible prophylactic mean of control against influenza viral infection.
Antiviral research 09/2011; 92(2):346-55. · 3.61 Impact Factor
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ABSTRACT: The prevalence of metabolic diseases associated with obesity, such as type 2 diabetes, continues to rise along with obesity rates. Recently, obesity has been described as an inflammatory condition, suggesting a link between the dysregulation in proinflammatory cytokine production and the aetiology of these metabolic diseases. While known as an immunomodulatory cytokine, Interleukin-15 (IL-15) has been shown to have effects on adipose tissue and induce weight loss in diet-induced obese mice. As weight loss improves glucose homeostasis, the goal of this study was to determine whether IL-15 impacts glucose regulation in a mouse model of diet-induced obesity. Our data demonstrate that IL-15 treatment significantly improves insulin sensitivity and glucose and insulin responses to an oral glucose challenge compared to obese counterparts and/or lean controls. These results show that IL-15 may be a novel therapeutic target for the treatment of obesity and its associated abnormal glucose regulation.
Diabetes Obesity and Metabolism 09/2011; 14(2):190-3. · 3.38 Impact Factor
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ABSTRACT: Sexually transmitted infections (STIs) are associated with increased human immunodeficiency virus type 1 (HIV-1) susceptibility and viral shedding in the genital tract, but the mechanisms underlying this association are poorly understood.
Direct activation of HIV long terminal repeats (LTRs), a proxy measure for HIV-1 replication, was measured after treatment of 1G5 T cells with Toll-like receptor (TLR) ligands, herpes simplex virus type 1 or 2 (HSV-1/2), or Neisseria gonorrhoeae. For indirect activation, 1G5 T cells were incubated with supernatants from female primary genital epithelial cells (GECs) previously exposed to these agents. Proinflammatory cytokines and chemokines were measured in GEC supernatants. Proinflammatory pathways were blocked to determine the mechanisms of direct and indirect HIV-LTR activation.
HSV-1/2, N. gonorrhoeae, and TLR ligands FimH (TLR-4), flagellin (TLR-5), and Poly (I:C) (TLR-3) directly induced HIV-LTR activation in 1G5 T cells. Supernatants collected from GECs incubated with these agents indirectly induced HIV-LTR activation. Production of tumor necrosis factor α, interleukin 6, interleukin 8, and monocyte chemoattractant protein-1 was elevated in GECs exposed to copathogens. Inhibition of nuclear factor κB and activator protein-1 (AP-1) signaling pathways in 1G5 T cells abrogated both direct and indirect HIV-LTR activation.
STIs may increase HIV-1 replication in the female genital tract via proinflammatory signaling pathways directly and indirectly via their effects on GECs. This increased HIV-1 replication may enhance sexual and vertical HIV transmission.
The Journal of Infectious Diseases 07/2011; 204(2):299-308. · 6.41 Impact Factor
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ABSTRACT: Salmonella enterica serovar Typhi (S. typhi), is a human restricted pathogen and the causal agent of typhoid fever. Although the use of antimicrobial drugs or vaccines has served as an effective therapeutics strategy against typhoid fever, the recent surge in multidrug resistant strains of S. typhi presents a major health concern worldwide. Progress on typhoid research has been limited in the past due to the lack of a suitable animal model that recapitulates the hallmark immunological features of human typhoid fever. We have recently developed a humanized immune system (HIS) mouse model that after intravenous challenge with S. typhi displayed classical manifestations of human typhoid fever including meningitis, liver pathology and mortality. Concurrent to our studies, two other groups also have developed humanized mouse models of S. typhi infections employing different protocols. All these recently adopted animal models of S. typhi infections provide promise for a new era of S. typhi research that may expedite detailed understanding of the cellular and molecular mechanisms of this bacterial infection and investigations of new antimicrobials and vaccines for effective control.
Virulence 05/2011; 2(3):248-52. · 2.26 Impact Factor
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ABSTRACT: Heterosexual transmission of HIV-1 and HSV-2 across the genital tract epithelial tissue is one of the primary routes for dissemination of these viral infections. Mucosal innate immunity is the first line of defense against invading pathogens. A vast majority of mucosal HIV-1 exposures do not result in productive infections which may indicate that the innate mucosal immune system is highly protective. It has been shown that Toll-like receptors (TLR)-induced innate antiviral immunity in the genital mucosa lead to induction of type I and III interferon and prevention of HSV-2 infection. The innate antiviral function of type I and III interferons and other innate factors at genital mucosa against HIV-1 is not well defined. In this review, we summarize our current understanding and advances of the innate mucosal response to genital viral infections, including HIV-1 and HSV-2, focusing on those factors that may prevent or accelerate initial infection. Understanding how each of these components contributes to mucosal innate antiviral immunity may lead to the development of novel and effective strategies to use microbicides or antiviral agents to control HIV-1 acquisition and/or transmission.
American Journal Of Reproductive Immunology 03/2011; 65(3):344-51. · 2.17 Impact Factor
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ABSTRACT: There is increasing evidence that natural killer (NK) cells play an important role in antitumor immunity following dendritic cell (DC) vaccination. Little is known, however, about the optimal stimulation of DCs that favors NK activation in tumor-bearing hosts. In this study, we demonstrate that treatment with toll-like receptor (TLR) ligands and infection with a mutant vesicular stomatitis virus (VSV-ΔM51) both induced DC maturation. Further, inoculation of these DCs led to robust NK-mediated protection against tumor challenge. Strikingly, only VSV-ΔM51-infected DCs were capable of suppressing the growth of established tumors, suggesting that additional signals provided by viral infection may be required to activate tumoricidal NK cells in tumor-bearing hosts. VSV-ΔM51 infection of DCs induced greater type I interferon (IFN I) production than TLR ligand treatment, and disruption of the IFN I pathway in DCs eliminated their ability to induce NK activation and tumor protection. However, further studies indicated that IFN I alone was not sufficient to activate NK cells, especially in the presence of a tumor, and DC-derived IL-15 was additionally required for tumoricidal NK activation. These results suggest that induction of IFN I by VSV-ΔM51 allows DCs to overcome tumor-associated immunosuppression and facilitate IL-15-mediated priming of tumoricidal NK cells. Thus, the mode of DC maturation should be carefully considered when designing DC-based cancer immunotherapies.
Cancer Research 02/2011; 71(7):2497-506. · 7.86 Impact Factor
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ABSTRACT: Herpes simplex virus type 2 (HSV-2) is becoming increasingly prevalent worldwide, despite the widespread use of antiviral drugs. Its ability to evade the immune system and establish a latent infection has made it difficult to develop an effective vaccine. Our understanding of the immune response against HSV-2 remains complex and involves a balance between innate signaling pathways and the adaptive immune response. Primary infection with HSV-2 induces toll-like receptor (TLR)-mediated Type I interferon (IFN) production, which establishes an antiviral state and activates multiple cell types, including natural killer cells and plasmacytoid dendritic cells. This innate response is not only crucial for controlling initial infection, but also for priming adaptive immune responses as well. Both humoral and cellular responses encompass adaptive immunity, although the former has been shown to be dispensable in response to HSV-2. Recently, numerous studies have attributed IFNγ producing CD4(+) T cells to be the key effector molecule responsible for clearing infection. It remains unclear whether regulatory T (Treg) cells are a source of aid or hindrance in the clearance of disease. Collectively, this review highlights the balance between innate and adaptive effector responses that contribute to the control and clearance of HSV-2 infection.
Journal of Reproductive Immunology 02/2011; 88(2):210-8. · 2.97 Impact Factor
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ABSTRACT: Innate antiviral immunity, particularly at mucosal surfaces, has a critical role in early control of viral infections. Both type I interferons (IFNs) and interleukin-15 (IL-15) are essential components of innate antiviral immunity. It has been shown that toll-like receptor (TLR) ligand-induced innate antiviral immunity requires IFN-α/β and -λ receptor signaling. However, it is not known if IL-15 has a role in TLR ligand-mediated antiviral responses. Here, we report that ligands for TLR-3 and TLR-9 cannot confer protection against genital herpes simplex virus-2 (HSV-2) in the absence of IL-15 in vivo. Interestingly, wild-type mice depleted of natural killer (NK) cells and treated with TLR ligands are protected upon HSV-2 challenge, suggesting that the critical role of IL-15 is independent of NK cell-mediated activity. To examine the cytokine response in the absence of IL-15, we investigated TLR ligand-induced IFN-β and -λ production in the vaginal washes, but found no impairment in IL-15(-/-) mice. Finally, we report no impairment in the expression of the IFN-stimulated genes in IL-15(-/-) mice. Collectively, the data suggest that TLR ligands induce an IFN-mediated response in the vaginal tract of both wild-type and IL-15(-/-) mice, but its induction is insufficient for providing protection against HSV-2 in the absence of IL-15.
Immunology and Cell Biology 02/2011; 89(6):663-9. · 3.66 Impact Factor
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ABSTRACT: Type I interferon (IFN) signalling, NK cells and NK cell-derived IFN-γ are critical in the early control of genital HSV-2 infection. We have recently reported that NK cells are the source of early IFN-γ in the genital tract in response to HSV-2. However, the response of NK cells to genital HSV-2 infection is not well defined in the context of type I IFN signalling. Here we show that HSV-2 replication was significantly higher in mice deficient in the type I IFN receptor or NK cells compared to wild type controls. There was no detectable IFN-γ production in the genital washes from IFN-α/βR(-/-) mice or NK cell depleted mice in response to HSV-2 infection compared to control mice. Absence of the type I IFN receptor does not alter homing of NK cells to the genital mucosa. Moreover, the absence of IL-12 had no significant effect on NK cell-derived IFN-γ. Surprisingly, IFN-α/βR(-/-) mice had more IL-15 positive cells in the genital mucosa in response to HSV-2 infection compared to control mice. We then examined the expression of IL-15 receptors on NK cells. There was no significant differences in the levels of IL-15 receptor expression on NK cells from IFN-α/βR(-/-) or control mice. Our data clearly suggest that type I IFN receptor signalling is essential for NK cell activation in response to genital HSV-2 infection, and propose that NK cell activation by IL-15 may involve type I IFNs.
Cellular Immunology 01/2011; 269(1):29-37. · 1.97 Impact Factor
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ABSTRACT: Evaluation of: Nakayama Y, Plisch EH, Sullivan JM et al. Role of PKR and type I IFNs in viral control during primary and secondary infection. PLoS Pathog. 6(6), e1000966 (2010). During acute viral infections, innate antiviral immunity has been extensively studied for its ability to inhibit and/or control viral replication while priming the adaptive immune system. Recently, these processes have been studied for their role in assisting adaptive immunity to effectively clear or control viral rechallenge. The paper under evaluation introduces the concept that functional innate immune mechanisms such as dsRNA-activated protein kinase (PKR) and type I interferons are critical in controlling viral replication during secondary lymphocyte choriomeningitis virus infection. Elegant adoptive transfer studies revealed that during lymphocyte choriomeningitis virus secondary infections, dependence of viral control relied on expression of these innate factors in virally infected cells and not in adaptive immune T cells. Such findings illustrate that functional adaptive responses are less effective in providing protection against reinfections in the absence of innate mechanisms. This demonstrates the importance of intact innate mechanisms when considering effective vaccine strategies.
Expert Review of Vaccines 10/2010; 9(10):1143-7. · 4.25 Impact Factor
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ABSTRACT: During activation, macrophages undergo physiological changes affecting their surface protein expression and cytokine production and have been subsequently categorized into M1 (classically-activated) and M2 (alternatively-activated) macrophages. It remains unclear which lymphocyte population provides the immune microenvironment to regulate macrophage polarization. In this study, we establish a functional and phenotypic profile of peritoneal macrophages from C57BL/6 wild-type mice. We also showed that Rag1(-/-) and Rag2(-/-)γc(-/-) mice have similar, exaggerated M1 characteristics in comparison to control mice, suggesting that NK and/or NK-T cells may not be essential in this process. By controlling for environmental factors, we determine that lymphocyte-derived cytokines, rather than inherent properties of macrophages themselves, are crucial for their regulation. Lastly, we report that macrophages from CD4(-/-) mice display an M1 profile, suggesting that CD4(+) T-cells play a dominant role over other lymphocyte populations in providing the cytokine environment for regulating macrophages towards an M2 profile under normal wild-type conditions.
Cellular Immunology 10/2010; 266(2):180-6. · 1.97 Impact Factor
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ABSTRACT: The innate immune system is crucial for host defense and immunosurveillance against pathogens and tumor cells. IL-15 is a pleiotropic cytokine with important effects on cells of the innate and adaptive immune systems. The NK cell- and CD8(+) T cell-mediated functions of IL-15 against tumor cells have been well documented. However, it has not been established whether IL-15 has innate anti-tumor functions independent of these cells. Here, we explored the innate anti-tumor potential of IL-15 using a B16F10 melanoma tumor model. IL-15tg mice exhibited significantly more resistance to tumor growth and metastasis compared to B6 mice, and to IL-15(-/-) mice, which exhibited increased susceptibility to B16F10 challenge. In vivo depletion of NK cells and CD8(+) T cells abrogated the innate resistance to B16F10 cells in B6 but not in IL-15tg mice. In addition, lung macrophages from IL-15tg mice produced significantly higher levels of NO and IL-12 compared with macrophages from B6 or IL-15(-/-) mice. To examine whether IL-15 has innate anti-tumor activity independent of NK cells and CD8(+) T cells, we developed Ad-Op-hIL-15; this resulted in significantly higher levels of biologically active hIL-15. Delivery of Ad-Op-hIL-15 into RAG-2(-/-)/gamma(c)(-/-) mice significantly suppressed tumor burden in the lungs compared with the control adenovirus vector. Our results show that IL-15 can have innate anti-tumor activity independent of NK cells and CD8(+) T cells and the common gamma(c)R.
Journal of leukocyte biology 09/2010; 88(3):529-36. · 4.99 Impact Factor
