RESUMO
Natural killer (NK) cells are innate immune cells able to rapidly kill virus-infected and tumor cells. Two NK cell populations are found in the blood; the majority (90%) expresses the CD16 receptor and also express the CD56 protein in intermediate levels (CD56(Dim) CD16(Pos)) while the remaining 10% are CD16 negative and express CD56 in high levels (CD56(Bright) CD16(Neg)). NK cells also reside in some tissues and traffic to various infected organs through the usage of different chemokines and chemokine receptors. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human virus that has developed numerous sophisticated and versatile strategies to escape the attack of immune cells such as NK cells. Here, we investigate whether the KSHV derived cytokine (vIL-6) and chemokines (vMIP-I, vMIP-II, vMIP-III) affect NK cell activity. Using transwell migration assays, KSHV infected cells, as well as fusion and recombinant proteins, we show that out of the four cytokine/chemokines encoded by KSHV, vMIP-II is the only one that binds to the majority of NK cells, affecting their migration. We demonstrate that vMIP-II binds to two different receptors, CX3CR1 and CCR5, expressed by naïve CD56(Dim) CD16(Pos) NK cells and activated NK cells, respectively. Furthermore, we show that the binding of vMIP-II to CX3CR1 and CCR5 blocks the binding of the natural ligands of these receptors, Fractalkine (Fck) and RANTES, respectively. Finally, we show that vMIP-II inhibits the migration of naïve and activated NK cells towards Fck and RANTES. Thus, we present here a novel mechanism in which KSHV uses a unique protein that antagonizes the activity of two distinct chemokine receptors to inhibit the migration of naïve and activated NK cells.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Movimento Celular/efeitos dos fármacos , Quimiocinas/farmacologia , Herpesvirus Humano 8/química , Células Matadoras Naturais/efeitos dos fármacos , Receptores de Quimiocinas/antagonistas & inibidores , Receptor 1 de Quimiocina CX3C , Células Cultivadas , Quimiocina CCL5/metabolismo , Quimiocina CX3CL1/metabolismo , Citocinas/genética , Citocinas/metabolismo , Humanos , Immunoblotting , Interleucina-6 , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Reação em Cadeia da Polimerase , Receptores CCR5/genética , Receptores CCR5/metabolismo , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismoRESUMO
Since miRNAs are considered non-immunogenic, it was not too surprising to discover that some herpesviruses, which are masters of immune evasion, developed their own unique miRNAs to escape immune elimination. In this point of view we discuss our recent findings in which we demonstrate that two polyomaviruses, JC and BK, use an identical miRNA to escape immune attack. This identical miRNA targets the stress-induced protein ULBP3, which is recognized by the killer receptor NKG2D and thus, through the usage of a miRNA, JCV and BKV avoid the NKG2D mediated elimination. We further compare the miRNA-based immune evasion mechanisms of herpes and polyomaviruses, offering new insights on the complexity of the stress induced ligands function and recognition. Lastly, we consider the possibility that other viral and cellular mechanisms are also involved in targeting ULBP3 and other NKG2D ligands.
Assuntos
Vírus BK/patogenicidade , Evasão da Resposta Imune , Vírus JC/patogenicidade , MicroRNAs/metabolismo , Infecções por Polyomavirus/virologia , RNA Viral/metabolismo , Vírus BK/genética , Vírus BK/imunologia , Proteínas Ligadas por GPI/metabolismo , Herpesviridae/genética , Herpesviridae/imunologia , Herpesviridae/patogenicidade , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Vírus JC/genética , Vírus JC/imunologia , MicroRNAs/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/imunologia , RNA Viral/genéticaRESUMO
Expression of the stress-induced ligands MICA, MICB and ULBP 1-6 are up-regulated as a cellular response to DNA damage, excessive proliferation or viral infection; thereby, they enable recognition and annihilation by immune cells that express the powerful activating receptor NKG2D. This receptor is present not exclusively, but primarily on NK cells. Knowledge about the regulatory mechanisms controlling ULBP expression is still vague. In this study, we report a direct interaction of the oncogenic RNA binding protein (RBP) IMP3 with ULBP2 mRNA, leading to ULBP2 transcript destabilization and reduced ULBP2 surface expression in several human cell lines. We also discovered that IMP3 indirectly targets MICB with a mechanism functionally distinct from that of ULBP2. Importantly, IMP3-mediated regulation of stress-ligands leads to impaired NK cell recognition of transformed cells. Our findings shed new light on the regulation of NKG2D ligands and on the mechanism of action of a powerful oncogenic RBP, IMP3.
Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Proteínas de Ligação a RNA/metabolismo , Evasão Tumoral , Linhagem Celular Tumoral , Proteínas Ligadas por GPI/antagonistas & inibidores , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Células Matadoras Naturais/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismoRESUMO
Natural Killer (NK) cells are innate immune lymphocytes specializing in recognition and killing of tumors and pathogens, using an array of activating and inhibitory receptors. NK inhibition is mediated by a large repertoire of inhibitory receptors, whereas a limited number of activating NK cell receptors execute NK cell activation. The ligands recognized by the activating receptors are stress-induced, pathogen derived, tumor specific and even self ligands. However, the full spectrum of NK cell receptors and ligands that control NK cell activity remains uncharacterized. Here we demonstrate that Paired Ig-Like type 2 Receptor Alpha (PILRα), binds a distinct human NK cell sub-population present in the peripheral blood and also in the decidua. We further demonstrate that the interaction of NK cells with PILRα expressing targets lead to elevated IFNγ secretion and cytotoxicity. In conclusion, we present here a novel NK activating ligand which binds and activates an unknown NK receptor expressed on a unique NK cell subset.
Assuntos
Antígeno CD56/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Receptores de Células Matadoras Naturais/metabolismo , Células Cultivadas , Citotoxicidade Imunológica , Células HEK293 , Humanos , Interferon gama/metabolismo , Ativação Linfocitária , Ligação ProteicaRESUMO
Polyomaviruses are a diverse family of viruses which are prevalent in the human population. However, the interactions of these viruses with the immune system are not well characterized. We have previously shown that two human polyomaviruses, JC and BK, use an identical microRNA to evade immune attack by Natural Killer (NK) cells. We showed that this viral microRNA suppresses ULBP3 expression, a stress induced ligand for the killer receptor NKG2D. Here we show that Simian Virus 40 (SV40) also evades NK cell attack through the down regulation of another stress-induced ligand of NKG2D, ULBP1. These findings indicate that NK cells play an essential role in fighting polyomavirus infections and further emphasize the importance of various members of the ULBP family in controlling polyomavirus infection.
Assuntos
Citotoxicidade Imunológica/imunologia , Evasão da Resposta Imune/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Células Matadoras Naturais/imunologia , Infecções por Polyomavirus/imunologia , Infecções Tumorais por Vírus/imunologia , Animais , Linhagem Celular , Regulação para Baixo , Proteínas Ligadas por GPI/biossíntese , Humanos , Vírus 40 dos Símios/imunologiaRESUMO
Natural killer (NK) cells form an important arm of the innate immune system and function to combat a wide range of invading pathogens, ranging from viruses to bacteria. However, the means by which NK cells accomplish recognition of pathogens with a limited repertoire of receptors remain largely unknown. In the current study, we describe the recognition of an emerging fungal pathogen, Candida glabrata, by the human NK cytotoxic receptor NKp46 and its mouse ortholog, NCR1. Using NCR1 knockout mice, we observed that this receptor-mediated recognition was crucial for controlling C. glabrata infection in vitro and in vivo. Finally, we delineated the fungal ligands to be the C. glabrata adhesins Epa1, Epa6, and Epa7 and demonstrated that clearance of systemic C. glabrata infections in vivo depends on their recognition by NCR1. As NKp46 and NCR1 have been previously shown to bind viral adhesion receptors, we speculate that NKp46/NCR1 may be a novel type of pattern recognition receptor.
Assuntos
Antígenos Ly/metabolismo , Candida glabrata/imunologia , Proteínas Fúngicas/metabolismo , Células Matadoras Naturais/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Animais , Antígenos Ly/genética , Candidíase/imunologia , Modelos Animais de Doenças , Humanos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptor 1 Desencadeador da Citotoxicidade Natural/genéticaRESUMO
Cells in our body can induce hundreds of antiviral genes following virus sensing, many of which remain largely uncharacterized. CEACAM1 has been previously shown to be induced by various innate systems; however, the reason for such tight integration to innate sensing systems was not apparent. Here, we show that CEACAM1 is induced following detection of HCMV and influenza viruses by their respective DNA and RNA innate sensors, IFI16 and RIG-I. This induction is mediated by IRF3, which bound to an ISRE element present in the human, but not mouse, CEACAM1 promoter. Furthermore, we demonstrate that, upon induction, CEACAM1 suppresses both HCMV and influenza viruses in an SHP2-dependent process and achieves this broad antiviral efficacy by suppressing mTOR-mediated protein biosynthesis. Finally, we show that CEACAM1 also inhibits viral spread in ex vivo human decidua organ culture.
Assuntos
Antígenos CD/metabolismo , Moléculas de Adesão Celular/metabolismo , Citomegalovirus/fisiologia , Orthomyxoviridae/fisiologia , Animais , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/virologia , Proteína DEAD-box 58/metabolismo , DNA Viral/metabolismo , Humanos , Influenza Humana/metabolismo , Influenza Humana/virologia , Fator Regulador 3 de Interferon/metabolismo , Camundongos , Técnicas de Cultura de Órgãos , Biossíntese de Proteínas , Receptores Imunológicos , Serina-Treonina Quinases TOR/metabolismo , Replicação ViralRESUMO
Natural killer cells (NK) are a component of innate immunity well known for their potent ability to kill virus-infected or neoplastically transformed cells following stimulation of the NK cell receptor NKG2D. One of the various ligands of NKG2D is MICB, a stress-induced ligand that has been found to be upregulated on the surface of tumor cells. However, there is little knowledge about how this upregulation may occur or how it may be selected against in tumors as a mechanism of immune escape. Here, we report that the metastasis-associated microRNA (metastamir) miR-10b directly binds to the 3' untranslated region of MICB and downregulates its expression. Notably, antagonizing miR-10b action enhanced NKG2D-mediated killing of tumor cells in vitro and enhanced clearance of tumors in vivo. Conversely, overexpression of miR-10b downregulated MICB and impaired elimination of tumor cells. Together, our results define MICB as a novel immune target of miR-10b, implying a direct link between metastasis capability and immune escape from NK cells.
Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Antígenos de Histocompatibilidade Classe I/biossíntese , Células Matadoras Naturais/metabolismo , MicroRNAs/metabolismo , Neoplasias/metabolismo , Animais , Linhagem Celular Tumoral , Regulação para Baixo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Células Matadoras Naturais/imunologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/imunologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/imunologia , Neoplasias/genética , Neoplasias/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Evasão Tumoral/genética , Evasão Tumoral/imunologiaRESUMO
The human polyoma viruses JCV and BKV establish asymptomatic persistent infection in 65%-90% of humans but can cause severe illness under immunosuppressive conditions. The mechanisms by which these viruses evade immune recognition are unknown. Here we show that a viral miRNA identical in sequence between JCV and BKV targets the stress-induced ligand ULBP3, which is a protein recognized by the killer receptor NKG2D. Consequently, viral miRNA-mediated ULBP3 downregulation results in reduced NKG2D-mediated killing of virus-infected cells by natural killer (NK) cells. Importantly, when the activity of the viral miRNA was inhibited during infection, NK cells killed the infected cells more efficiently. Because NKG2D is also expressed by various T cell subsets, we propose that JCV and BKV use an identical miRNA that targets ULBP3 to escape detection by both the innate and adaptive immune systems, explaining how these viruses remain latent without being eliminated by the immune system.