Stipan Jonjic
Publications
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8.98Impact points
Degradation of cellular mir-27 by a novel, highly abundant viral transcript is important for efficient virus replication in vivo.
PLoS pathogens. 02/2012; 8(2):e1002510.
Cytomegaloviruses express large amounts of viral miRNAs during lytic infection, yet, they only modestly alter the cellular miRNA profile. The most prominent alteration upon lytic murine cytomegalovirus (MCMV) infection is the rapid degradation of the cellular miR-27a and miR-27b. Here, we report tha... [more] Cytomegaloviruses express large amounts of viral miRNAs during lytic infection, yet, they only modestly alter the cellular miRNA profile. The most prominent alteration upon lytic murine cytomegalovirus (MCMV) infection is the rapid degradation of the cellular miR-27a and miR-27b. Here, we report that this regulation is mediated by the ∼1.7 kb spliced and highly abundant MCMV m169 transcript. Specificity to miR-27a/b is mediated by a single, apparently optimized, miRNA binding site located in its 3'-UTR. This site is easily and efficiently retargeted to other cellular and viral miRNAs by target site replacement. Expression of the 3'-UTR of m169 by an adenoviral vector was sufficient to mediate its function, indicating that no other viral factors are essential in this process. Degradation of miR-27a/b was found to be accompanied by 3'-tailing and -trimming. Despite its dramatic effect on miRNA stability, we found this interaction to be mutual, indicating potential regulation of m169 by miR-27a/b. Most interestingly, three mutant viruses no longer able to target miR-27a/b, either due to miRNA target site disruption or target site replacement, showed significant attenuation in multiple organs as early as 4 days post infection, indicating that degradation of miR-27a/b is important for efficient MCMV replication in vivo.
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5.15Impact points
The NK cell response to mouse cytomegalovirus infection affects the level and kinetics of the early CD8(+) T-cell response.
Journal of virology. 12/2011; 86(4):2165-75.
Natural killer (NK) cells and CD8(+) T cells play a prominent role in the clearance of mouse cytomegalovirus (MCMV) infection. The role of NK cells in modulating the CD8(+) T-cell response to MCMV infection is still the subject of intensive research. For analyzing the impact of NK cells on mounting ... [more] Natural killer (NK) cells and CD8(+) T cells play a prominent role in the clearance of mouse cytomegalovirus (MCMV) infection. The role of NK cells in modulating the CD8(+) T-cell response to MCMV infection is still the subject of intensive research. For analyzing the impact of NK cells on mounting of a CD8(+) T-cell response and the contribution of these cells to virus control during the first days postinfection (p.i.), we used C57BL/6 mice in which NK cells are specifically activated through the Ly49H receptor engaged by the MCMV-encoded ligand m157. Our results indicate that the requirement for CD8(+) T cells in early MCMV control inversely correlates with the engagement of Ly49H. While depletion of CD8(+) T cells has only a minor effect on the early control of wild-type MCMV, CD8(+) T cells are essential in the control of Δm157 virus. The frequencies of virus epitope-specific CD8(+) T cells and their activation status were higher in mice infected with Δm157 virus. In addition, these mice showed elevated levels of alpha interferon (IFN-α) and several other proinflammatory cytokines as early as 1.5 days p.i. Although the numbers of conventional dendritic cells (cDCs) were reduced later during infection, particularly in Δm157-infected mice, they were not significantly affected at the peak of the cytokine response. Altogether, we concluded that increased antigen load, preservation of early cDCs' function, and higher levels of innate cytokines collectively account for an enhanced CD8(+) T-cell response in C57BL/6 mice infected with a virus unable to activate NK cells via the Ly49H-m157 interaction.
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11.05Impact points
All is fair in virus-host interactions: NK cells and cytomegalovirus.
Trends in molecular medicine. 08/2011; 17(11):677-85.
The infection of mice with mouse cytomegalovirus (MCMV) as a model of human cytomegalovirus (HCMV) infection has been particularly informative in elucidating the role of innate and adaptive immune response mechanisms during infection. Millions of years of co-evolution between cytomegaloviruses (CMV)... [more] The infection of mice with mouse cytomegalovirus (MCMV) as a model of human cytomegalovirus (HCMV) infection has been particularly informative in elucidating the role of innate and adaptive immune response mechanisms during infection. Millions of years of co-evolution between cytomegaloviruses (CMV) and their hosts has resulted in numerous attempts to overwhelm each other. CMVs devote many genes to modulating the host natural killer (NK) cell response and NK cells employ many strategies to cope with CMV infection. While focusing on these attack-counterattack measures, this review will discuss several novel mechanisms of immune evasion by MCMV, the role of Ly49 receptors in mediating resistance to MCMV, and the impact of the initial NK cell response on the shaping of adaptive immunity.
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5.15Impact points
Virus progeny of murine cytomegalovirus bacterial artificial chromosome pSM3fr show reduced growth in salivary Glands due to a fixed mutation of MCK-2.
Journal of virology. 08/2011; 85(19):10346-53.
Murine cytomegalovirus (MCMV) Smith strain has been cloned as a bacterial artificial chromosome (BAC) named pSM3fr and used for analysis of virus gene functions in vitro and in vivo. When sequencing the complete BAC genome, we identified a frameshift mutation within the open reading frame (ORF) enco... [more] Murine cytomegalovirus (MCMV) Smith strain has been cloned as a bacterial artificial chromosome (BAC) named pSM3fr and used for analysis of virus gene functions in vitro and in vivo. When sequencing the complete BAC genome, we identified a frameshift mutation within the open reading frame (ORF) encoding MCMV chemokine homologue MCK-2. This mutation would result in a truncated MCK-2 protein. When mice were infected with pSM3fr-derived virus, we observed reduced virus production in salivary glands, which could be reverted by repair of the frameshift mutation. When looking for the source of the mutation, we consistently found that virus stocks of cell culture-passaged MCMV Smith strain are mixtures of viruses with or without the MCK-2 mutation. We conclude that the MCK-2 mutation in the pSM3fr BAC is the result of clonal selection during the BAC cloning procedure.
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5.15Impact points
Reversible inhibition of murine cytomegalovirus replication by gamma interferon (IFN-γ) in primary macrophages involves a primed type I IFN-signaling subnetwork for full establishment of an immediate-early antiviral state.
Journal of virology. 07/2011; 85(19):10286-99.
Activated macrophages play a central role in controlling inflammatory responses to infection and are tightly regulated to rapidly mount responses to infectious challenge. Type I interferon (alpha/beta interferon [IFN-α/β]) and type II interferon (IFN-γ) play a crucial role in activating macrophages ... [more] Activated macrophages play a central role in controlling inflammatory responses to infection and are tightly regulated to rapidly mount responses to infectious challenge. Type I interferon (alpha/beta interferon [IFN-α/β]) and type II interferon (IFN-γ) play a crucial role in activating macrophages and subsequently restricting viral infections. Both types of IFNs signal through related but distinct signaling pathways, inducing a vast number of interferon-stimulated genes that are overlapping but distinguishable. The exact mechanism by which IFNs, particularly IFN-γ, inhibit DNA viruses such as cytomegalovirus (CMV) is still not fully understood. Here, we investigate the antiviral state developed in macrophages upon reversible inhibition of murine CMV by IFN-γ. On the basis of molecular profiling of the reversible inhibition, we identify a significant contribution of a restricted type I IFN subnetwork linked with IFN-γ activation. Genetic knockout of the type I-signaling pathway, in the context of IFN-γ stimulation, revealed an essential requirement for a primed type I-signaling process in developing a full refractory state in macrophages. A minimal transient induction of IFN-β upon macrophage activation with IFN-γ is also detectable. In dose and kinetic viral replication inhibition experiments with IFN-γ, the establishment of an antiviral effect is demonstrated to occur within the first hours of infection. We show that the inhibitory mechanisms at these very early times involve a blockade of the viral major immediate-early promoter activity. Altogether our results show that a primed type I IFN subnetwork contributes to an immediate-early antiviral state induced by type II IFN activation of macrophages, with a potential further amplification loop contributed by transient induction of IFN-β.
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14.51Impact points
Distinct MHC class I-dependent NK cell-activating receptors control cytomegalovirus infection in different mouse strains.
The Journal of experimental medicine. 05/2011; 208(5):1105-17.
Recognition of mouse cytomegalovirus (MCMV)-infected cells by activating NK cell receptors was first described in the context of Ly49H, which confers resistance to C57BL/6 mice. We investigated the ability of other activating Ly49 receptors to recognize MCMV-infected cells in mice from various H-2 b... [more] Recognition of mouse cytomegalovirus (MCMV)-infected cells by activating NK cell receptors was first described in the context of Ly49H, which confers resistance to C57BL/6 mice. We investigated the ability of other activating Ly49 receptors to recognize MCMV-infected cells in mice from various H-2 backgrounds. We observed that Ly49P1 from NOD/Ltj mice, Ly49L from BALB mice, and Ly49D2 from PWK/Pas mice respond to MCMV-infected cells in the context of H-2D(k) and the viral protein m04/gp34. Recognition was also seen in the H-2(d) and/or H-2(f) contexts, depending on the Ly49 receptor examined, but never in H-2(b). Furthermore, BALB.K (H-2(k)) mice showed reduced viral loads compared with their H-2(d) or H-2(b) congenic partners, a reduction which was dependent on interferon γ secretion by Ly49L(+) NK cells early after infection. Adoptive transfer of Ly49L(+), but not Ly49L(-), NK cells significantly increased resistance against MCMV infection in neonate BALB.K mice. These results suggest that multiple activating Ly49 receptors participate in H-2-dependent recognition of MCMV infection, providing a common mechanism of NK cell-mediated resistance against viral infection.
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20.59Impact points
Resistance to mousepox virus: CD94 on a special mission.
Immunity. 04/2011; 34(4):458-60.
NK cells play a key role in the control of ectromelia virus. In this issue of Immunity, Fang et al. (2011) demonstrate that the deletion of CD94 abolishes resistance to mousepox infection.... [more] NK cells play a key role in the control of ectromelia virus. In this issue of Immunity, Fang et al. (2011) demonstrate that the deletion of CD94 abolishes resistance to mousepox infection.
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3.91Impact points
Deletion of galectin-3 in the host attenuates metastasis of murine melanoma by modulating tumor adhesion and NK cell activity.
Clinical & experimental metastasis. 03/2011; 28(5):451-62.
Galectin-3, a β galactoside-binding lectin, plays an important role in the processes relevant to tumorigenesis such as malignant cell transformation, invasion and metastasis. We have investigated whether deletion of Galectin-3 in the host affects the metastasis of B16F1 malignant melanoma. Galectin-... [more] Galectin-3, a β galactoside-binding lectin, plays an important role in the processes relevant to tumorigenesis such as malignant cell transformation, invasion and metastasis. We have investigated whether deletion of Galectin-3 in the host affects the metastasis of B16F1 malignant melanoma. Galectin-3-deficient (Gal-3(-/-)) mice are more resistant to metastatic malignant melanoma as evaluated by number and size of metastatic colonies in the lung. In vitro assays showed lower number of attached malignant cells in the tissue section derived from Gal-3(-/-) mice. Furthermore, lack of Galectin-3 correlates with higher serum levels of IFN-γ and IL-17 in tumor bearing hosts. Interestingly, spleens of Gal-3(-/-) mice have lower number of Foxp3(+) T cells after injection of B16F1 melanoma cells. Finally, we found that while CD8(+) T cell and adherent cell cytotoxicity were similar, there was greater cytotoxic activity of splenic NK cells of Gal-3(-/-) mice compared with "wild-type" (Gal-3( +/+ )) mice. Despite the reduction in total number of CD3ε(-)NK1.1(+), Gal-3(-/-) mice constitutively have a significantly higher percentage of effective cytotoxic CD27(high)CD11b(high) NK cells as well as the percentage of immature CD27(high)CD11b(low) NK cells. In contrast, CD27(low)CD11b(high) less functionally exhausted NK cells and NK cells bearing inhibitory KLRG1 receptor were more numerous in Gal-3( +/+ ) mice. It appears that lack of Galectin-3 affects tumor metastasis by at least two independent mechanisms: by a decrease in binding of melanoma cells onto target tissue and by enhanced NK-mediated anti-tumor response suggesting that Galectin-3 may be considered as therapeutic target.
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26.00Impact points
Natural killer cells: fighting viruses and much more.
Nature immunology. 02/2011; 12(2):107-10.
More than 450 immunologists recently met in Cavtat, Croatia to discuss advances in natural killer (NK) cell biology. The meeting highlighted emerging themes in NK cell responses to viruses, NK cell tolerance and potential use of NK cells in the therapy of malignancies.... [more] More than 450 immunologists recently met in Cavtat, Croatia to discuss advances in natural killer (NK) cell biology. The meeting highlighted emerging themes in NK cell responses to viruses, NK cell tolerance and potential use of NK cells in the therapy of malignancies.
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Manipulation of NKG2D Ligands by Cytomegaloviruses: Impact on Innate and Adaptive Immune Response.
Frontiers in immunology. 01/2011; 2:85.
NKG2D is a potent activating receptor expressed on NK cells, NKT cells, γδ T cells, and CD8 T cells. NKG2D recognizes cell surface molecules structurally related to MHC class I proteins induced by infection or other type of cellular stress. The engagement of NKG2D leads to NK cell cytotoxicity and c... [more] NKG2D is a potent activating receptor expressed on NK cells, NKT cells, γδ T cells, and CD8 T cells. NKG2D recognizes cell surface molecules structurally related to MHC class I proteins induced by infection or other type of cellular stress. The engagement of NKG2D leads to NK cell cytotoxicity and cytokine secretion or to a co-stimulation of CD8 T cells. Both human and mouse cytomegalovirus (CMV) have evolved numerous mechanisms to evade NKG2D-mediated immune response. This review describes the mechanisms used by CMV to inhibit NKG2D ligand expression and the recent advances in exploiting the NKG2D recognition pathway for mounting efficient and long-lasting immune response.
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15.39Impact points
Recombinant mouse cytomegalovirus expressing a ligand for the NKG2D receptor is attenuated and has improved vaccine properties.
The Journal of clinical investigation. 12/2010; 120(12):4532-45.
Human CMV (HCMV) is a major cause of morbidity and mortality in both congenitally infected and immunocompromised individuals. Development of an effective HCMV vaccine would help protect these vulnerable groups. NK group 2, member D (NKG2D) is a potent activating receptor expressed by cells of the in... [more] Human CMV (HCMV) is a major cause of morbidity and mortality in both congenitally infected and immunocompromised individuals. Development of an effective HCMV vaccine would help protect these vulnerable groups. NK group 2, member D (NKG2D) is a potent activating receptor expressed by cells of the innate and adaptive immune systems. Its importance in HCMV immune surveillance is indicated by the elaborative evasion mechanisms evolved by the virus to avoid NKG2D. In order to study this signaling pathway, we engineered a recombinant mouse CMV expressing the high-affinity NKG2D ligand RAE-1γ (RAE-1γMCMV). Expression of RAE-1γ by MCMV resulted in profound virus attenuation in vivo and lower latent viral DNA loads. RAE-1γMCMV infection was efficiently controlled by immunodeficient hosts, including mice lacking type I interferon receptors or immunosuppressed by sublethal γ-irradiation. Features of MCMV infection in neonates were also diminished. Despite tight innate immune control, RAE-1γMCMV infection elicited strong and long-lasting protective immunity. Maternal RAE-1γMCMV immunization protected neonatal mice from MCMV disease via placental transfer of antiviral Abs. Despite strong selective pressure, the RAE-1γ transgene did not exhibit sequence variation following infection. Together, our results indicate that use of a recombinant virus encoding the ligand for an activating NK cell receptor could be a powerful approach to developing a safe and immunogenic HCMV vaccine.
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14.51Impact points
Cytomegalovirus immunoevasin reveals the physiological role of "missing self" recognition in natural killer cell dependent virus control in vivo.
The Journal of experimental medicine. 11/2010; 207(12):2663-73.
Cytomegaloviruses (CMVs) are renowned for interfering with the immune system of their hosts. To sidestep antigen presentation and destruction by CD8(+) T cells, these viruses reduce expression of major histocompatibility complex class I (MHC I) molecules. However, this process sensitizes the virus-i... [more] Cytomegaloviruses (CMVs) are renowned for interfering with the immune system of their hosts. To sidestep antigen presentation and destruction by CD8(+) T cells, these viruses reduce expression of major histocompatibility complex class I (MHC I) molecules. However, this process sensitizes the virus-infected cells to natural killer (NK) cell-mediated killing via the "missing self" axis. Mouse cytomegalovirus (MCMV) uses m152 and m06 encoded proteins to inhibit surface expression of MHC I molecules. In addition, it encodes another protein, m04, which forms complexes with MHC I and escorts them to the cell surface. This mechanism is believed to prevent NK cell activation and killing by restoring the "self" signature and allowing the engagement of inhibitory Ly49 receptors on NK cells. Here we show that MCMV lacking m04 was attenuated in an NK cell- and MHC I-dependent manner. NK cell-mediated control of the infection was dependent on the presence of NK cell subsets expressing different inhibitory Ly49 receptors. In addition to providing evidence for immunoevasion strategies used by CMVs to avoid NK cell control via the missing-self pathway, our study is the first to demonstrate that missing self-dependent NK cell activation is biologically relevant in the protection against viral infection in vivo.
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5.65Impact points
Expression and function of CD300 in NK cells.
Journal of immunology (Baltimore, Md. : 1950). 09/2010; 185(5):2877-86.
The killing activity of NK cells is regulated by signals derived from inhibitory and activating NK cell receptors, including the CD300 family of proteins. CD300a was reported to be expressed on all NK cells and to deliver an inhibitory signal upon binding to a yet unknown ligand/s. The CD300a protei... [more] The killing activity of NK cells is regulated by signals derived from inhibitory and activating NK cell receptors, including the CD300 family of proteins. CD300a was reported to be expressed on all NK cells and to deliver an inhibitory signal upon binding to a yet unknown ligand/s. The CD300a protein contains four ITIMs and is highly homologous to CD300c. Little is known about the function and distribution of these two receptors and the identity of their ligand/s. In this article, we show that CD300a is indeed an inhibitory receptor expressed by human NK cells, but surprisingly, we show that not all NK clones are inhibited in a CD300a-dependent manner. We demonstrate, using a panel of 13 new anti-CD300a and CD300c Abs that we generated, that CD300a and CD300c are indistinguishable on the surface of NK cells. Using mutational-analysis survey, we show that tyrosine 267 located in the third ITIM motif of the CD300a protein is important for the inhibitory function of CD300a.
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7.87Impact points
Modulation of natural killer cell activity by viruses.
Current opinion in microbiology. 08/2010; 13(4):530-9.
Since their discovery, our understanding of NK cells has evolved from branding them marginal innate immunity cells to key players in anti-viral and anti-tumor immunity. Importance of NK cells in control of various viral infections is perhaps best illustrated by the existence of plethora of viral mec... [more] Since their discovery, our understanding of NK cells has evolved from branding them marginal innate immunity cells to key players in anti-viral and anti-tumor immunity. Importance of NK cells in control of various viral infections is perhaps best illustrated by the existence of plethora of viral mechanisms aimed to modulate their function. These mechanisms include not only virally encoded immunoevasion proteins but also viral miRNA. Moreover, the evidence has been accumulated supporting the role of viral immunoevasion of NK cells in viral pathogenesis in vivo.
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5.65Impact points
Intact NKG2D-independent function of NK cells chronically stimulated with the NKG2D ligand Rae-1.
Journal of immunology (Baltimore, Md. : 1950). 07/2010; 185(1):157-65.
Human tumors frequently express membrane-bound or soluble NK group 2, member D (NKG2D) ligands. This results in chronic engagement of NKG2D on the surfaces of NK and CD8(+) T cells and rapid internalization of the receptor. Although it is well appreciated that this phenomenon impairs NKG2D-dependent... [more] Human tumors frequently express membrane-bound or soluble NK group 2, member D (NKG2D) ligands. This results in chronic engagement of NKG2D on the surfaces of NK and CD8(+) T cells and rapid internalization of the receptor. Although it is well appreciated that this phenomenon impairs NKG2D-dependent function, careful analysis of NKG2D-independent functions in cells chronically stimulated through NKG2D is lacking. Using a mouse model of chronic NKG2D ligand expression, we show that constant exposure to NKG2D ligands does not functionally impair NK cells and CD8(+) T cells in the context of viral infection.
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5.18Impact points
Functional plasticity and robustness are essential characteristics of biological systems: lessons learned from KLRG1-deficient mice.
European journal of immunology. 04/2010; 40(5):1241-3.
Killer cell lectin-like receptor G1 (KLRG1) receptor is considered to be a marker of terminally differentiated NK and T cells and is strongly induced by viral and other infections. KLRG1 is a C-type lectin-like inhibitory receptor, which interacts with members of the cadherin family of molecules lea... [more] Killer cell lectin-like receptor G1 (KLRG1) receptor is considered to be a marker of terminally differentiated NK and T cells and is strongly induced by viral and other infections. KLRG1 is a C-type lectin-like inhibitory receptor, which interacts with members of the cadherin family of molecules leading to the inhibition of T- and NK-cell function. A study in this issue of the European Journal of Immunology addresses the role of KLRG1 in the maturation and differentiation of NK and T cells in vivo. Using KLRG1-deficient mice generated by homologous recombination, the study reveals that KLRG1 is dispensable for NK- and CD8+ T-cell differentiation and function in vivo. This interesting finding is discussed in this Commentary in light of the plasticity and robustness of immune response mechanisms.
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8.98Impact points
Cytomegalovirus microRNAs facilitate persistent virus infection in salivary glands.
PLoS pathogens. 01/2010; 6(10):e1001150.
Micro (mi)RNAs are small non-coding RNAs that regulate the expression of their targets' messenger RNAs through both translational inhibition and regulation of target RNA stability. Recently, a number of viruses, particularly of the herpesvirus family, have been shown to express their own miRNAs ... [more] Micro (mi)RNAs are small non-coding RNAs that regulate the expression of their targets' messenger RNAs through both translational inhibition and regulation of target RNA stability. Recently, a number of viruses, particularly of the herpesvirus family, have been shown to express their own miRNAs to control both viral and cellular transcripts. Although some targets of viral miRNAs are known, their function in a physiologically relevant infection remains to be elucidated. As such, no in vivo phenotype of a viral miRNA knock-out mutant has been described so far. Here, we report on the first functional phenotype of a miRNA knock-out virus in vivo. During subacute infection of a mutant mouse cytomegalovirus lacking two viral miRNAs, virus production is selectively reduced in salivary glands, an organ essential for virus persistence and horizontal transmission. This phenotype depends on several parameters including viral load and mouse genetic background, and is abolished by combined but not single depletion of natural killer (NK) and CD4+ T cells. Together, our results point towards a miRNA-based immunoevasion mechanism important for long-term virus persistence.
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9.43Impact points
The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity.
Proceedings of the National Academy of Sciences of the United States of America. 10/2009;
NK cell cytotoxicity is controlled by numerous NK inhibitory and activating receptors. Most of the inhibitory receptors bind MHC class I proteins and are expressed in a variegated fashion. It was recently shown that TIGIT, a new protein expressed by T and NK cells binds to PVR and PVR-like receptors... [more] NK cell cytotoxicity is controlled by numerous NK inhibitory and activating receptors. Most of the inhibitory receptors bind MHC class I proteins and are expressed in a variegated fashion. It was recently shown that TIGIT, a new protein expressed by T and NK cells binds to PVR and PVR-like receptors and inhibits T cell activity indirectly through the manipulation of DC activity. Here, we show that TIGIT is expressed by all human NK cells, that it binds PVR and PVRL2 but not PVRL3 and that it inhibits NK cytotoxicity directly through its ITIM. Finally, we show that TIGIT counter inhibits the NK-mediated killing of tumor cells and protects normal cells from NK-mediated cytoxicity thus providing an "alternative self" mechanism for MHC class I inhibition.
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20.59Impact points
Altered NK Cell Development and Enhanced NK Cell-Mediated Resistance to Mouse Cytomegalovirus in NKG2D-Deficient Mice.
Immunity. 08/2009;
NKG2D is a potent activating receptor on natural killer (NK) cells and acts as a molecular sensor for stressed cells expressing NKG2D ligands such as infected or tumor-transformed cells. Although NKG2D is expressed on NK cell precursors, its role in NK cell development is not known. We have generate... [more] NKG2D is a potent activating receptor on natural killer (NK) cells and acts as a molecular sensor for stressed cells expressing NKG2D ligands such as infected or tumor-transformed cells. Although NKG2D is expressed on NK cell precursors, its role in NK cell development is not known. We have generated NKG2D-deficient mice by targeting the Klrk1 locus. Here we provide evidence for an important regulatory role of NKG2D in the development of NK cells. The absence of NKG2D caused faster division of NK cells, perturbation in size of some NK cell subpopulations, and their augmented sensitivity to apoptosis. As expected, Klrk1(-/-) NK cells are less responsive to tumor targets expressing NKG2D ligands. Klrk1(-/-) mice, however, showed an enhanced NK cell-mediated resistance to mouse cytomegalovirus infection as a consequence of NK cell dysregulation. Altogether, these findings provide evidence for regulatory function of NKG2D in NK cell physiology.
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5.15Impact points
Differential susceptibility of RAE-1 isoforms to mouse cytomegalovirus.
Journal of virology. 07/2009;
The NKG2D receptor is one of the most potent activating NK cell receptors involved in antiviral responses. Mouse NKG2D ligands, MULT-1, RAE-1 and H60 are regulated by mouse cytomegalovirus (MCMV) proteins m145, m152 and m155, respectively. In addition, the m138 protein interferes with the expression... [more] The NKG2D receptor is one of the most potent activating NK cell receptors involved in antiviral responses. Mouse NKG2D ligands, MULT-1, RAE-1 and H60 are regulated by mouse cytomegalovirus (MCMV) proteins m145, m152 and m155, respectively. In addition, the m138 protein interferes with the expression of both MULT-1 and H60. Here we show that one of five RAE-1 isoforms, RAE-1delta, is resistant to down-regulation by MCMV and that this escape has functional importance in vivo. Although m152 retained newly synthesized RAE-1delta and RAE-1gamma in the endoplasmic reticulum, no viral regulator was able to affect the mature RAE-1delta form which remains expressed on the surface of infected cells. This differential susceptibility to down-regulation by MCMV is not a consequence of faster maturation of RAE-1delta as compared to RAE-1gamma but rather an intrinsic property of the mature surface-resident protein. This difference can be attributed to the absence of a PLWY motif from RAE-1delta. Altogether, these findings provide evidence for a novel mechanism of host escape from viral immunoevasion of NKG2D-dependent control.
Following (16)
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Francesca Levi-Schaffer
The Hebrew University of Jerusalem -
Birgit Strobl
University of Veterinary Medicine Vienna -
Sheila Kothe
Neurochirurgie -
Dirk Busch
Technische Universität München -
Luka Cicin-Sain
Helmholtz-Zentrum für Infektionsforschung
67
Publications
19
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