scholarly journals Evasion of the Cell-Mediated Immune Response by Alphaherpesviruses

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1354
Author(s):  
Naoto Koyanagi ◽  
Yasushi Kawaguchi
Keyword(s):  
Immune Response ◽  
Natural Killer ◽  
Immune Evasion ◽  
Immune Cells ◽  
Target Cells ◽  
Latent Infections ◽  
Viral Propagation ◽  
Host Immune Responses ◽  
Cell Mediated Immune Response

Alphaherpesviruses cause various diseases and establish life-long latent infections in humans and animals. These viruses encode multiple viral proteins and miRNAs to evade the host immune response, including both innate and adaptive immunity. Alphaherpesviruses evolved highly advanced immune evasion strategies to be able to replicate efficiently in vivo and produce latent infections with recurrent outbreaks. This review describes the immune evasion strategies of alphaherpesviruses, especially against cytotoxic host immune responses. Considering these strategies, it is important to evaluate whether the immune evasion mechanisms in cell cultures are applicable to viral propagation and pathogenicity in vivo. This review focuses on cytotoxic T lymphocytes (CTLs), natural killer cells (NK cells), and natural killer T cells (NKT cells), which are representative immune cells that directly damage virus-infected cells. Since these immune cells recognize the ligands expressed on their target cells via specific activating and/or inhibitory receptors, alphaherpesviruses make several ligands that may be targets for immune evasion. In addition, alphaherpesviruses suppress the infiltration of CTLs by downregulating the expression of chemokines at infection sites in vivo. Elucidation of the alphaherpesvirus immune evasion mechanisms is essential for the development of new antiviral therapies and vaccines.

scholarly journals Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells

2021 ◽  
Vol 17 (11) ◽  
pp. e1010034
Author(s):  
Opeyemi S. Adeniji ◽  
Leticia Kuri-Cervantes ◽  
Chenfei Yu ◽  
Ziyang Xu ◽  
Michelle Ho ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Evasion ◽  
Neutralizing Antibodies ◽  
Target Cells ◽  
Inhibitory Receptor ◽  
Infected Cells

Siglec-9 is an MHC-independent inhibitory receptor expressed on a subset of natural killer (NK) cells. Siglec-9 restrains NK cytotoxicity by binding to sialoglycans (sialic acid-containing glycans) on target cells. Despite the importance of Siglec-9 interactions in tumor immune evasion, their role as an immune evasion mechanism during HIV infection has not been investigated. Using in vivo phenotypic analyses, we found that Siglec-9+ CD56dim NK cells, during HIV infection, exhibit an activated phenotype with higher expression of activating receptors and markers (NKp30, CD38, CD16, DNAM-1, perforin) and lower expression of the inhibitory receptor NKG2A, compared to Siglec-9- CD56dim NK cells. We also found that levels of Siglec-9+ CD56dim NK cells inversely correlate with viral load during viremic infection and CD4+ T cell-associated HIV DNA during suppressed infection. Using in vitro cytotoxicity assays, we confirmed that Siglec-9+ NK cells exhibit higher cytotoxicity towards HIV-infected cells compared to Siglec-9- NK cells. These data are consistent with the notion that Siglec-9+ NK cells are highly cytotoxic against HIV-infected cells. However, blocking Siglec-9 enhanced NK cells’ ability to lyse HIV-infected cells, consistent with the known inhibitory function of the Siglec-9 molecule. Together, these data support a model in which the Siglec-9+ CD56dim NK subpopulation is highly cytotoxic against HIV-infected cells even whilst being restrained by the inhibitory effects of Siglec-9. To harness the cytotoxic capacity of the Siglec-9+ NK subpopulation, which is dampened by Siglec-9, we developed a proof-of-concept approach to selectively disrupt Siglec/sialoglycan interactions between NK and HIV-infected cells. We achieved this goal by conjugating Sialidase to several HIV broadly neutralizing antibodies. These conjugates selectively desialylated HIV-infected cells and enhanced NK cells’ capacity to kill them. In summary, we identified a novel, glycan-based interaction that may contribute to HIV-infected cells’ ability to evade NK immunosurveillance and developed an approach to break this interaction.

Engineered natural killer cells impede the immunometabolic CD73-adenosine axis in solid tumors

2021 ◽  
Author(s):  
Andrea Marie Chambers ◽  
Kyle Byrnes Lupo ◽  
Jiao Wang ◽  
Jingming Cao ◽  
Sandra Toregrosa-Allen ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Immune Evasion ◽  
Immune Cells ◽  
Nk Cell ◽  
Purinergic Signaling ◽  
Single Agent ◽  
Antibody Specificity

Immunometabolic reprogramming due to CD73-produced adenosine is a recognized immunosuppressive mechanism contributing to immune evasion in solid tumors. Adenosine is not only known to contribute to tumor progression, but it has specific roles in driving dysfunction of immune cells, including natural killer (NK) cells. Here, we engineered NK cells to directly target the CD73-adenosine axis by blocking the enzymatic activity of CD73. In doing so, the engineered NK cells not only impaired adenosinergic metabolism driven by the hypoxic uptake of ATP by cancer cells, but also mediated killing of tumor cells due to the specific recognition of overexpressed CD73. This results in a "single agent" immunotherapy that combines antibody specificity, blockade of purinergic signaling, and killing of targets mediated by NK cells. We also showed that CD73-targeted NK cells are potent in vivo and result in tumor arrest, while promoting NK cell infiltration into CD73+ tumors and enhanced intratumoral activation.

scholarly journals Slow viral propagation during initial phase of infection leads to viral persistence in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Haifeng C. Xu ◽  
Ruifeng Wang ◽  
Prashant V. Shinde ◽  
Lara Walotka ◽  
Anfei Huang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Evasion ◽  
Protein Transport ◽  
Adaptive Immune System ◽  
Viral Persistence ◽  
Lymphocytic Choriomeningitis ◽  
Type I ◽  
Viral Propagation

AbstractImmune evasion of pathogens can modify the course of infection and impact viral persistence and pathology. Here, using different strains of the lymphocytic choriomeningitis virus (LCMV) model system, we show that slower propagation results in limited type I interferon (IFN-I) production and viral persistence. Specifically, cells infected with LCMV-Docile exhibited reduced viral replication when compared to LCMV-WE and as a consequence, infection with LCMV-Docile resulted in reduced activation of bone marrow derived dendritic cells (BMDCs) and IFN-I production in vitro in comparison with LCMV-WE. In vivo, we observed a reduction of IFN-I, T cell exhaustion and viral persistence following infection of LCMV-Docile but not LCMV-WE. Mechanistically, block of intracellular protein transport uncovered reduced propagation of LCMV-Docile when compared to LCMV-WE. This reduced propagation was critical in blunting the activation of the innate and adaptive immune system. When mice were simultaneously infected with LCMV-Docile and LCMV-WE, immune function was restored and IFN-I production, T cell effector functions as well as viral loads were similar to that of mice infected with LCMV-WE alone. Taken together, this study suggests that reduced viral propagation can result in immune evasion and viral persistence.

scholarly journals Impact of Influenza A Virus Shutoff Proteins on Host Immune Responses

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 629
Author(s):  
Megan M. Dunagan ◽  
Kala Hardy ◽  
Toru Takimoto
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Influenza A Virus ◽  
Influenza A ◽  
Human Populations ◽  
Lymphocyte Migration ◽  
Host Immune Responses ◽  
Mhc Molecules ◽  
The Impact

Influenza A virus (IAV) is a significant human pathogen that causes seasonal epidemics. Although various types of vaccines are available, IAVs still circulate among human populations, possibly due to their ability to circumvent host immune responses. IAV expresses two host shutoff proteins, PA-X and NS1, which antagonize the host innate immune response. By transcriptomic analysis, we previously showed that PA-X is a major contributor for general shutoff, while shutoff active NS1 specifically inhibits the expression of host cytokines, MHC molecules, and genes involved in innate immunity in cultured human cells. So far, the impact of these shutoff proteins in the acquired immune response in vivo has not been determined in detail. In this study, we analyzed the effects of PA-X and NS1 shutoff activities on immune response using recombinant influenza A/California/04/2009 viruses containing mutations affecting the expression of shutoff active PA-X and NS1 in a mouse model. Our data indicate that the virus without shutoff activities induced the strongest T and B cell responses. Both PA-X and NS1 reduced host immune responses, but shutoff active NS1 most effectively suppressed lymphocyte migration to the lungs, antibody production, and the generation of IAV specific CD4+ and CD8+ T cells. NS1 also prevented the generation of protective immunity against a heterologous virus challenge. These data indicate that shutoff active NS1 plays a major role in suppressing host immune responses against IAV infection.

scholarly journals Natural killer-mediated lysis of normal and malignant target cells, and its regulation by monocytes.

1985 ◽  
Vol 162 (2) ◽  
pp. 472-486 ◽  
Author(s):  
K Oshimi ◽  
Y Oshimi ◽  
M Satake ◽  
H Mizoguchi
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
B Lymphocytes ◽  
Leukemia Cells ◽  
Target Cells ◽  
Large Granular Lymphocytes ◽  
Percoll Density Gradient ◽  
Granular Lymphocytes ◽  
Density Gradient Sedimentation

After depletion of monocytes, natural killer (NK) cells were partially purified from peripheral blood by Percoll density gradient sedimentation. The NK cells were then cultured for 1 d and assayed for their cytotoxicity against various types of normal and malignant target cells. All types of target cells tested were found to be susceptible to NK cells. The susceptible targets were autologous T and B lymphocytes, mitogen-induced T and B blasts, monocytes, large granular lymphocytes, autologous or allogeneic lymphoma and leukemia cells isolated from patients, and cultured cell lines, including those resistant to interferon-activated lymphocytes. Such a broad spectrum of cytotoxicity was demonstrated in 1 d of culture, and freshly prepared NK cells were not cytotoxic, or, if anything, were less cytotoxic. Monocytes and their supernatants, added throughout the course of culture, markedly inhibited the development of their cytotoxicity. These results may suggest that, although NK cells having ability to lyse autologous normal and malignant target cells are present in vivo, their lytic activity is regulated by coexisting monocytes.

scholarly journals Tetherin Promotes the Innate and Adaptive Cell–Mediated Immune Response against Retrovirus Infection In Vivo

2014 ◽  
Vol 193 (1) ◽  
pp. 306-316 ◽  
Author(s):  
Sam X. Li ◽  
Bradley S. Barrett ◽  
Karl J. Heilman ◽  
Ronald J. Messer ◽  
Rachel A. Liberatore ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Mediated Immune Response ◽  
Retrovirus Infection

scholarly journals Selective response to H-Y antigen by F1 female mice sensitized to F1 male cells.

1977 ◽  
Vol 146 (2) ◽  
pp. 606-610 ◽  
Author(s):  
R D Gordon ◽  
L E Samelson ◽  
E Simpson
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Target Cells ◽  
Gene Products ◽  
Gene Complex ◽  
Suppressor Genes ◽  
Cytotoxic Responses ◽  
Major Histocompatibility Gene

T-cell mediated cytotoxic responses to H-Y antigen require co-recognition of H-Y and H-2 gene products. F1 mael stimulating cells and target cells express H-Y antigen in association with both parental H-2 haplotypes. However, F1 females primed in vivo and challenged in vitro with F1 male cells lyse male target cells of F1 and only one parental H-2 haplotype. Thus, (CBA X B10)F1 females sensitized to (CBA X B10)F1 male cells lyse (CBA X B10)F1 and CBA but not B10 male target cells, and (BALB/c X B10)F1 females sensitized to (BALB/c X B10)F1 male cells will lyse (BALB/c X B10)F1 and B10 but not BALB/c male target cells. It is suggested that this may represent an effect of immune response or suppressor genes mapping in the major histocompatibility gene complex which regulate responsiveness to H-Y antigen.

Molecular Basis of Lymphocyte-Mediated Destruction of Traget Cells

Physiology ◽  
1988 ◽  
Vol 3 (5) ◽  
pp. 211-216
Author(s):  
JD-E Young ◽  
ZA Cohn
Keyword(s):  
Natural Killer Cells ◽  
T Lymphocytes ◽  
Natural Killer ◽  
Cytotoxic T Lymphocytes ◽  
Immune Cells ◽  
Molecular Basis ◽  
Target Cells ◽  
Killer Cells

Subsets of lymphocytes, known as cytotoxic T lymphocytes or natural killer cells, are potent killers of target cells. These immune cells have large granules in their cytoplasm containing cytotoxic peptides and other factors. Several of these molecules have been isolated and their functions elucidated.

scholarly journals The immunoregulation of mesenchymal stem cells plays a critical role in improving the prognosis of liver transplantation

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Chenxia Hu ◽  
Lanjuan Li
Keyword(s):  
Liver Transplantation ◽  
Natural Killer ◽  
Immune Cells ◽  
Adaptive Systems ◽  
Critical Role ◽  
Arterial System ◽  
Cell Mediated Immunity ◽  
Adaptive Immune Cells

AbstractThe liver is supplied by a dual blood supply, including the portal venous system and the hepatic arterial system; thus, the liver organ is exposed to multiple gut microbial products, metabolic products, and toxins; is sensitive to extraneous pathogens; and can develop liver failure, liver cirrhosis and hepatocellular carcinoma (HCC) after short-term or long-term injury. Although liver transplantation (LT) serves as the only effective treatment for patients with end-stage liver diseases, it is not very popular because of the complications and low survival rates. Although the liver is generally termed an immune and tolerogenic organ with adaptive systems consisting of humoral immunity and cell-mediated immunity, a high rejection rate is still the main complication in patients with LT. Growing evidence has shown that mesenchymal stromal cell (MSC) transplantation could serve as an effective immunomodulatory strategy to induce tolerance in various immune-related disorders. MSCs are reported to inhibit the immune response from innate immune cells, including macrophages, dendritic cells (DCs), natural killer cells (NK cells), and natural killer T (NKT) cells, and that from adaptive immune cells, including T cells, B cells and other liver-specific immune cells, for the generation of a tolerogenic microenvironment. In this review, we summarized the relationship between LT and immunoregulation, and we focused on how to improve the effects of MSC transplantation to improve the prognosis of LT. Only after exhaustive clarification of the potential immunoregulatory mechanisms of MSCs in vitro and in vivo can we implement MSC protocols in routine clinical practice to improve LT outcome.

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