NATURAL KILLER CELLS IN ANTIVIRAL DEFENSE: Function and Regulation by Innate Cytokines

Biron, Christine A.; Nguyen, Khuong B.; Pien, Gary C.; Cousens, Leslie P.; Salazar-Mather, Thais P.

doi:10.1146/annurev.immunol.17.1.189

Cited by 1,886 publications

(1,502 citation statements)

References 242 publications

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“…2C) that are strong NK-cell stimulators [31,32], we examined whether NK cell-activating agents may delay tumor development in vivo through an NK cellmediated mechanism. We therefore treated clinically unapparent l-myc mice with CpG-ODN 1668 for several weeks.…”

Section: Nk-cell Activation Delays Lymphoma Development In K-myc Micementioning

confidence: 99%

Requirements for control of B‐cell lymphoma by NK cells

et al. 2010

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The role of NK cells in the control of endogenously arising tumors is still unclear. We monitored activation and effector functions of NK cells in a c‐myc‐transgenic mouse model of spontaneously arising lymphoma. At early stages, tumors demonstrated reduced MHC class I expression and increased expression of natural killer group 2D ligands (NKG2D‐L). NK cells in these tumors showed an activated phenotype that correlated with the loss of tumor MHC class I. With increasing tumor load however, NK‐cell effector functions became progressively paralyzed or exhausted. In later stages of disease, tumors re‐expressed MHC class I and lost NKG2D‐L, suggesting a role of these two signals for NK cell‐mediated tumor control. Testing a panel of lymphoma cell lines expressing various MHC class I and NKG2D‐L levels suggested that NK cell‐dependent tumor control required a priming and a triggering signal that were provided by MHC class I down‐regulation and by NKG2D‐L, respectively. Deleting either of the “two signals” resulted in tumor escape. At early disease stages, immune stimulation through TLR‐ligands in vivo efficiently delayed lymphoma growth in a strictly NK cell‐dependent manner. Thus, NK‐receptor coengagement is crucial for NK‐cell functions in vivo and especially for NK cell‐mediated tumor surveillance.

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Section: Nk-cell Activation Delays Lymphoma Development In K-myc Micementioning

confidence: 99%

Requirements for control of B‐cell lymphoma by NK cells

et al. 2010

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“…In addition to cytotoxic properties, NK cells have immunoregulatory functions. Through the expression of cell surface molecules and the secretion of cytokines such as IFN-g, they directly modulate macrophages, B and T lymphocyte and DC functions [11,12,14,15]. Consequently, in addition to a protective role in anti-tumor and antiviral immunity, it is now suggested that NK cells may play a role in inflammation, autoimmune disorders and hematopoietic and solid organ transplantation [11].…”

Section: Introductionmentioning

confidence: 99%

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

et al. 2009

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NK lymphocytes and type I IFN (IFN-a/b) are major actors of the innate anti-viral response that also influence adaptive immune responses. We evaluated type I IFN production by human NK cells in response to polyI:C, a potent type I IFN-inducing TLR3 agonist. PolyI:C plus IL-2/IL-12 induced IFN-b (but not IFN-a) mRNA expression and protein production by highly pure human NK cells and by the human NK cell line NK92. Neutralizing anti-IFNAR1 or anti-IFN-b Ab prevented the production of IFN-c induced by polyI:C plus IL-2/IL-12. Similarly, IFN-c production induced by polyI:C plus IL-12 was reduced in NK cells isolated from IFNAR1 À/À compared with WT mice. The ability of polyI:C plus IL-12 to induce IFN-c production was related to an increase of TLR3, Mda5 and IFNAR expression and by an increase of STAT1 and STAT4 phosphorylation. Collectively, these data demonstrate that NK cells, in response to polyI:C plus IL-2/IL-12, produce IFN-b that induce, in an autocrine manner, the production of IFN-c and thereby highlight that NK cells may control the outcome of protective or injurious immune responses through type I IFN secretion.Key words: IFN-g . NK cells . PolyI:C . Type I IFN IntroductionType I IFN is a multi-member cytokine family, in which IFN-a and -b are the main types of interest from an immunological perspective [1,2]. They are involved in anti-viral immunity and in some immune disorders (such as autoimmune diseases). In addition to directly interfering with viral replication, type I IFN have anti-proliferative and immunoregulatory properties. They bridge innate and adaptive immune responses by inducing DC maturation and favoring antigen cross-presentation [3]. They also act directly on CD8 1 T cells to favor the generation of effector and memory T cells [4]. The expression of type I IFN is induced early upon recognition of viruses or viral moieties by some innate receptors of the TLR or RIG-1-like receptor families [5]. IFN-a is mainly secreted by plasmacytoid DC in response to viral nucleic acids recognized by TLR7 and 9 [6]. IFN-b mRNA expression is induced in numerous cell types by TLR stimulation [7,8]. IFN-b has a short half-time, is difficult to quantify, and its secretion is mainly evidenced indirectly by neutralizing its activity in in vitro assay [9]. Owing to the central role of type I IFN in the [11]. These cells kill virally infected cells and tumoral cells in the absence of prior activation [11,12]. NK-cell cytotoxic activity is tightly regulated by inhibitory and activatory receptors [13]. Consequently, NK cells are important during the early phases of viral infection, while antigen-specific T-and B-cell responses are generated. In addition to cytotoxic properties, NK cells have immunoregulatory functions. Through the expression of cell surface molecules and the secretion of cytokines such as IFN-g, they directly modulate macrophages, B and T lymphocyte and DC functions [11,12,14,15]. Consequently, in addition to a protective role in anti-tumor and antiviral immunity, it is now suggested that NK c...

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“…1,2 The KIR receptors can be grouped into three distinct lineages based on the configuration of the extracellular immunoglobulin (Ig)-like domains. 3 The first lineage comprises two Ig domain-containing KIRs with D0-D2 configuration (KIR2DL4 and 2DL5), the second lineage comprises three Ig domain containing KIRs with D0-D1-D2 configuration (KIR3DL1-3 and 3DS1) and the third lineage comprises two Ig domain containing KIRs with D1-D2 configuration (KIR2DL1-3 and 2DS1-5).…”

Section: Introductionmentioning

confidence: 99%

KIR2DL5 alleles mark certain combination of activating KIR genes

Sharma

Spellman

et al. 2008

Genes Immun

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Killer cell Ig-like receptors (KIR) control the immune response of NK cells and some T cells to infections and tumors. KIR genes evolve rapidly and are variable between individuals in their number, type and sequence. Here, we determined the nature of KIR2DL5 gene polymorphism in four ethnic groups using direct DNA sequencing method. Nine new sequences were discovered. Within the panel of 248 KIR2DL5-positive individuals, 14 KIR2DL5-sequences differing in coding regions were observed. They differed at only seven amino acid positions, and such limited polymorphism is consistent with its conserved nature throughout the hominoid lineage. Ethnic deviation was seen in the distribution of KIR2DL5A, KIR2DL5B and their alleles. African Americans had more KIR2DL5 alleles than other populations indicating that more polymorphisms are yet to be discovered in Africans. Linkage between KIR2DL5-alleles and certain activating-KIR genes were observed, but frequency of these linked clusters differed substantially between populations. Consequently, KIR2DL5 alleles can be used as markers to predict the activating-KIR gene content. Typing system distinguishing A*001 and B*002 alleles can serve as a powerful screening test to assess the content of most variable activating-KIR genes that have been implicated in human disease and in the outcome of hematopoietic stem cell transplantation.

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NATURAL KILLER CELLS IN ANTIVIRAL DEFENSE: Function and Regulation by Innate Cytokines

Cited by 1,886 publications

References 242 publications

Requirements for control of B‐cell lymphoma by NK cells

Requirements for control of B‐cell lymphoma by NK cells

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

KIR2DL5 alleles mark certain combination of activating KIR genes

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