Emerging insights into human health and <scp>NK</scp> cell biology from the study of <scp>NK</scp> cell deficiencies

Mace, Emily M.; Orange, Jordan S.

doi:10.1111/imr.12725

Cited by 135 publications

(116 citation statements)

References 239 publications

(516 reference statements)

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“…Natural killer cell deficiencies are reportedly associated with severe viral infections, including EBV . However, the in‐depth investigation of these conditions shows that (a) they are not selective for NK cells, and (b) they include a T cell deficiency (such as GATA‐2 or MCM4 deficiency) in most (but not all) cases .…”

Section: Primary Immunodeficiencies (Pids) and Ebvmentioning

confidence: 99%

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Latour

Fischer

2019

Immunological Reviews

113

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Primary immunodeficiencies (PIDs) provide researchers with unique models to understand in vivo immune responses in general and immunity to infections in particular. In humans, impaired immune control of Epstein-Barr virus (EBV) infection is associated with the occurrence of several different immunopathologic conditions; these include non-malignant and malignant B-cell lymphoproliferative disorders, hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory condition, and a chronic acute EBV infection of T cells. Studies of PIDs associated with a predisposition to develop severe, chronic EBV infections have led to the identification of key components of immunity to EBV -notably the central role of T-cell expansion and its regulation in the pathophysiology of EBV-associated diseases. On one hand, the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4-1BB)) leads to impaired elimination of proliferating EBV-infected B cells and the occurrence of lymphoma. On the other hand, protracted T-cell expansion and activation after the defective killing of EBV-infected B cells is caused by genetic defects in the components of the lytic granule exocytosis pathway or in the small adapter protein SH2D1A (also known as SAP), a key activator of T-and NK cell-cytotoxicity. In this setting, the persistence of EBV-infected cells results in HLH, a condition characterized by unleashed T-cell and macrophage activation. Moreover, genetic defects causing selective vulnerability to EBV infection have highlighted the role of co-receptor molecules (CD27, CD137, and SLAM-R) selectively involved in immune responses against infected B cells via specific T-B cell interactions. K E Y W O R D S B-cell lymphoproliferation, cell-cytotoxicity, Epstein-Barr virus, hemophagocytic lymphohistiocytosis, primary immunodeficiency, T-cell proliferation | IMMUNE RE S P ON S E S TO EBV INFEC TI ONEpstein-Barr virus (EBV, also known as human herpesvirus 4) is a gamma herpes virus that only infects primates (primarily humans). 1,2 It is an encapsidated, double-stranded DNA virus with more than 100 genes. It is pandemic, since the great majority of human beings (>90%) have been infected by EBV. The main cell target is B lymphocytes that express CD21 -the membrane receptor for EBV entry through its 350 kDa major envelope glycoprotein. In immunocompetent adolescents and adults, EBV infection causes infectious mononucleosis (IM). Immunologically speaking, IM is characterized by a This article is part of a series of reviews covering Signaling and Signal Diversification in Immune

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Section: Primary Immunodeficiencies (Pids) and Ebvmentioning

confidence: 99%

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Latour

Fischer

2019

Immunological Reviews

113

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“…NK cells play a key role in the clearance of virus‐infected cells and the pathogenesis of many diseases 1–3 . The type 1 cytokine IL‐12 provokes a canonical IFN‐γ response by NK cells 4 .…”

Section: Introductionmentioning

confidence: 99%

“…NK cells play a key role in the clearance of virus-infected cells and the pathogenesis of many diseases. [1][2][3] The type 1 cytokine IL-12 provokes a canonical IFN-response by NK cells. 4 Other type 1 cytokines, including IL-15, IL-18, and IL-1 enhance IL-12-induced IFN-release by NK cells.…”

Section: Introductionmentioning

confidence: 99%

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

Ochayon

Ali

Alarcon

et al. 2020

Journal of Leukocyte Biology

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This study tests the hypothesis that activation of MAPK by physiologically relevant concentrations of IL‐33 contributes to enhanced cytokine expression by IL‐12 stimulated human NK cells. While IL‐33 canonically triggers type 2 cytokine responses, this cytokine can also synergize with type 1 cytokines like IL‐12 to provoke IFN‐γ. We show that picogram concentrations of IL‐12 and IL‐33 are sufficient to promote robust secretion of IFN‐γ by human NK cells that greatly exceeds resposes to either cytokine alone. Nanogram doses of IL‐33, potentially consistent with levels in tissue microenvironments, synergize with IL‐12 to induce secretion of additional cytokines, including TNF and GM‐CSF. IL‐33‐induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN‐γ and TNF in response to IL‐12. Mechanistically, IL‐33‐induced p38 MAPK signaling enhances stability of IFNG transcripts and triggers A disintegrin and metalloproteinase domain 17 (ADAM17) mediated cleavage of TNF from the cell surface. These data support our hypothesis and suggest that altered sensitivity of NK cells to IL‐12 in the presence of IL‐33 may have important consequences in diseases associated with mixed cytokine milieus, like asthma and chronic obstructive pulmonary disease.

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“…In this regard, more than 60% of NKD patients are infected by one of these viruses (Orange, 2013), also in the context of intact CTL functions (Quinnan et al, 1982). The severity of this condition is demonstrated by the fact that nearly half of patients with NKD tend to die prematurely (Orange, 2013;Mace and Orange, 2019).…”

Section: Nk Cells and Hcmv: A Balance Of Opposing Forcesmentioning

confidence: 99%

Tuning the Orchestra: HCMV vs. Innate Immunity

et al. 2020

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Understanding how the innate immune system keeps human cytomegalovirus (HCMV) in check has recently become a critical issue in light of the global clinical burden of HCMV infection in newborns and immunodeficient patients. Innate immunity constitutes the first line of host defense against HCMV as it involves a complex array of cooperating effectors -e.g., inflammatory cytokines, type I interferon (IFN-I), natural killer (NK) cells, professional antigen-presenting cells (APCs) and phagocytes -all capable of disrupting HCMV replication. These factors are known to trigger a highly efficient adaptive immune response, where cellular restriction factors (RFs) play a major gatekeeping role. Unlike other innate immunity components, RFs are constitutively expressed in many cell types, ready to act before pathogen exposure. Nonetheless, the existence of a positive regulatory feedback loop between RFs and IFNs is clear evidence of an intimate cooperation between intrinsic and innate immunity. In the course of virushost coevolution, HCMV has, however, learned how to manipulate the functions of multiple cellular players of the host innate immune response to achieve latency and persistence. Thus, HCMV acts like an orchestra conductor able to piece together and rearrange parts of a musical score (i.e., innate immunity) to obtain the best live performance (i.e., viral fitness). It is therefore unquestionable that innovative therapeutic solutions able to prevent HCMV immune evasion in congenitally infected infants and immunocompromised individuals are urgently needed. Here, we provide an up-to-date review of the mechanisms regulating the interplay between HCMV and innate immunity, focusing on the various strategies of immune escape evolved by this virus to gain a fitness advantage.

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Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

Cited by 135 publications

References 239 publications

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

Tuning the Orchestra: HCMV vs. Innate Immunity

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