Genetic dissection of NK cell responses

Moussa, Peter; Marton, Jennifer; Vidal, Silvia M.; Fodil-Cornu, Nassima

doi:10.3389/fimmu.2012.00425

Cited by 7 publications

(11 citation statements)

References 106 publications

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“…The activation of NK cells is determined by a delicate balance of signals delivered by inhibitory and activating receptors (27). While inhibitory receptors engage ubiquitously expressed MHC class I molecules, activating receptors recognize stress-induced ligands (27,28). During viral infections, alterations in the balance of these signals, such as MHC class I downregulation and/or upregulation of ligands recognized by activating receptors, result in NK cell activation.…”

Section: Natural Killer-mediated Control Of Mouse Cytomegalovirus Infmentioning

confidence: 99%

“…Instead, humans have a family of receptors called the killer cell immunoglobulin-like receptors (KIRs) that are functionally analogous to the Ly49 receptors. Similar to mouse Ly49H, the human activating KIR, NKG2D controls HCMV infection (28). However, NKG2D does not recognize virally encoded proteins but instead binds to stress-induced MHC class I-related molecules, such as MICA/MICB, that are induced as a result of infection (43).…”

Section: Natural Killer-mediated Control Of Mouse Cytomegalovirus Infmentioning

confidence: 99%

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Mapping Viral Susceptibility Loci in Mice

Kane

Golovkina

2019

Annu. Rev. Virol.

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Genetic alleles that contribute to enhanced susceptibility or resistance to viral infections and virally induced diseases have often been first identified in mice before humans due to the significant advantages of the murine system for genetic studies. Herein we review multiple discoveries that have revealed significant insights into virus-host interactions, all made using genetic mapping tools in mice. Factors that have been identified include innate and adaptive immunity genes that contribute to host defense against pathogenic viruses such as herpes viruses, flaviviruses, retroviruses, and coronaviruses. Understanding the genetic mechanisms that affect infectious disease outcomes will aid the development of personalized treatment and preventive strategies for pathogenic infections.

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Section: Natural Killer-mediated Control Of Mouse Cytomegalovirus Infmentioning

confidence: 99%

Section: Natural Killer-mediated Control Of Mouse Cytomegalovirus Infmentioning

confidence: 99%

Mapping Viral Susceptibility Loci in Mice

Kane

Golovkina

2019

Annu. Rev. Virol.

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“…Despite the ongoing discovery of genetic variants associated with immunodeficiency and susceptibility to autoimmune disease and infection, the genetic control of the human immune system, particularly under homeostatic conditions, remains poorly understood [71,72]. Genetic approaches have led to the identification of genes that modulate NK cell development, recognition and cytotoxicity, which are likely to influence NK cell therapy [71,72]. For instance, the proportion of NK cells varies between individuals, representing 5-15% of circulating lymphoid cells, and such variation is, in part, heritable [73,74].…”

Section: The Genetic Backgroundmentioning

confidence: 99%

“…Thus, the engagement of inhibitory KIRs with self HLA-I molecules educates or "licenses" NK cells for function [95]. KIR-HLA class I combinations significantly affect NK cell activity, ADCC and prognosis [96,97], and they have a significant impact on infection outcomes and autoimmune disease susceptibility [72]. In the same line of evidence, KIR polymorphisms and HLA class I alleles have been shown to be involved in the efficacy of anti-GD2 mAb-based therapy in children with high-risk neuroblastomas [96,98] and in the efficacy of rituximab in FL [99].…”

Section: The Genetic Backgroundmentioning

confidence: 99%

Mechanisms of Resistance to NK Cell Immunotherapy

Sordo‐Bahamonde

Vitale

Lorenzo‐Herrero

et al. 2020

Cancers

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Immunotherapy has recently been a major breakthrough in cancer treatment. Natural killer (NK) cells are suitable targets for immunotherapy owing to their potent cytotoxic activity that may target cancer cells in a major histocompatibility complex (MHC) and antigen-unrestricted manner. Current therapies targeting NK cells include monoclonal antibodies that promote NK cell antibody-dependent cell-mediated cytotoxicity (ADCC), hematopoietic stem cell transplantation (HSCT), the adoptive transfer of NK cells, the redirection of NK cells using chimeric antigen receptor (CAR)-NK cells and the use of cytokines and immunostimulatory drugs to boost the anti-tumor activity of NK cells. Despite some encouraging clinical results, patients receiving these therapies frequently develop resistance, and a myriad of mechanisms of resistance affecting both the immune system and cancer cells have been reported. A first contributing factor that modulates the efficacy of the NK cell therapy is the genetic profile of the individual, which regulates all aspects of NK cell biology. Additionally, the resistance of cancer cells to apoptosis and the immunoediting of cancer cells, a process that decreases their immunogenicity and promotes immunosuppression, are major determinants of the resistance to NK cell therapy. Consequently, the efficacy of NK cell anti-tumor therapy is specific to each patient and disease. The elucidation of such immunosubversive mechanisms is crucial to developing new procedures and therapeutic strategies to fully harness the anti-tumor potential of NK cells.

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“…In C57BL/6 mice, NK cells expressing the activating receptor Ly49H are responsible for the control of MCMV replication 20 21 . Ly49H binds to the viral glycoprotein m157 which is expressed at the surface of infected cells within hours of infection 22 . This binding triggers signaling pathways that activate NK cell effector functions such as IFNγ secretion, release of cytotoxic granules containing perforin and granzymeB, as wells as proliferation of Ly49H+ NK cell subsets 22 .…”

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confidence: 99%

Reduced MCMV Δm157 viral clearance in the absence of TSAd

Moussa

Abrahamsen

Fodil

et al. 2015

Sci Rep

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The T cell specific adapter protein (TSAd) is expressed in activated T cells and NK cells. While TSAd is beginning to emerge as a critical regulator of Lck and Itk activity in T cells, its role in NK cells has not yet been explored. Here we have examined susceptibility to virus infections in a murine model using various viral infection models. We report that TSAd-deficient mice display reduced clearance of murine cytomegalovirus (MCMV) that lack the viral MHC class I homologue m157, which is critical for Ly49H-mediated NK cell recognition of infected cells. In this infection model, NK cells contribute in the early stages of the disease, whereas CD8+ T cells are critical for viral clearance. We found that mice infected with MCMV Δm157 displayed reduced viral clearance in the spleen as well as reduced proliferation in spleen NK cells and CD8+ T cells in the absence of TSAd. Though no other immunophenotype was detected in the infection models tested, these data suggests that in the absence of the Ly49H ligand activation, NK cell and CD8+ T cell responses may be compromised in TSAd-deficient mice.

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Genetic dissection of NK cell responses

Cited by 7 publications

References 106 publications

Mapping Viral Susceptibility Loci in Mice

Mapping Viral Susceptibility Loci in Mice

Mechanisms of Resistance to NK Cell Immunotherapy

Reduced MCMV Δm157 viral clearance in the absence of TSAd

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