Human cytomegalovirus escapes immune recognition by NK cells through the downregulation of B7-H6 by the viral genes US18 and US20

Charpak-Amikam, Yoav; Kubsch, Tobias; Seidel, Einat; Oiknine‐Djian, Esther; Cavaletto, Noemi; Yamin, Rachel; Schmiedel, Dominik; Wolf, Dana; Gribaudo, Giorgio; Messerle, Martin; Čičin-Šain, Luka; Mandelboim, Ofer

doi:10.1038/s41598-017-08866-2

Cited by 41 publications

(28 citation statements)

References 44 publications

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“…The virus used in HCMV infection experiments is an HCMV TB40/e_GFP mutant strain deleted for the genomic region encompassing US17-20. The Virus was generated and grown as previously described [8]. For the infection, 50,000 cells were grown overnight in a 24-well plate.…”

Section: Resultsmentioning

confidence: 99%

“…To examine whether physiological ER stress also results in B7H6 induction, we infected the melanoma cells with human cytomegalovirus (HCMV), a virus that causes ER stress upon infection [29]. Curiously, HCMVevolved molecular strategies to downregulate B7H6 by the viral proteins US18 and US20 [7,8], which can negate ER stress-mediated induction. A total of 624 wt and PERK KO cells were infected with the HCMV ΔUS17-20 mutant, which lacks the modulators of B7H6.…”

Section: Hcmv Upregulates B7h6 In a Perk-dependent Mannermentioning

confidence: 99%

“…B7H6 is also important for fighting viral infections. Some viruses, such as the human cytomegalovirus (HCMV) and the human herpesvirus 6, evolve mechanisms to downregulate B7H6, a strategy that probably helps to escape immune detection [7][8][9]. Other viruses not equipped with these machineries, such as the human immunodeficiency virus 2 (HIV-2), confer the upregulation of B7H6 [10].…”

Section: Introductionmentioning

confidence: 99%

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The integrated stress response promotes B7H6 expression

et al. 2019

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The B7 family member, B7H6, is a ligand for the natural killer cell receptor NKp30. B7H6 is hardly expressed on normal tissues, but undergoes upregulation on different types of tumors, implicating it as an attractive target for cancer immunotherapy. The molecular mechanisms that control B7H6 expression are poorly understood. We report that in contrast to other NK cell ligands, endoplasmic reticulum (ER) stress upregulates B7H6 mRNA levels and surface expression. B7H6 induction by ER stress requires protein kinase R-like ER kinase (PERK), one of the three canonical sensors of the unfolded protein response. PERK phosphorylates eIF2α, which regulates protein synthesis and gene expression. Because eIF2α is phosphorylated by several kinases following different stress conditions, the program downstream to eIF2α phosphorylation is called the integrated stress response (ISR). Several drugs were reported to promote the ISR. Nelfinavir and lopinavir, two clinically approved HIV protease inhibitors, promote eIF2α phosphorylation by different mechanisms. We show that nelfinavir and lopinavir sustainably instigate B7H6 expression at their pharmacologically relevant concentrations. As such, ER stress and ISR conditions sensitize melanoma targets to CART cells directed against B7H6. Our study highlights a novel mechanism to induce B7H6 expression and suggests a pharmacological approach to improve B7H6-directed immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Section: Hcmv Upregulates B7h6 In a Perk-dependent Mannermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The integrated stress response promotes B7H6 expression

et al. 2019

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“…ULBP3 is instead targeted by UL142, also blocking MICA expression (Ashiru et al, 2009;Bennett et al, 2010). The ability to simultaneously evade multiple cellular pathways has also been reported for US18 and US20, capable of inhibiting both MICA and the NKp30 ligand B7-H6 (Charpak-Amikam et al, 2017;Fielding et al, 2017).…”

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

confidence: 93%

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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“…For example, HCMV targets NKp30 both by suppressing the expression of cellular NKp30 ligands and by interfering with NKp30-mediated signaling. On the one hand, HCMV US18 and US20, which also target MICA (see above), were found to suppress cell surface expression of the NKp30 ligand B7-H6 (42,68). As in the case of MICA, B7-H6 downregulation involves lysosomal degradation and results in impaired NK cell activation (42).…”

Section: Herpesvirus Nk Cell Evasion Strategiesmentioning

confidence: 98%

Herpesvirus Evasion of Natural Killer Cells

Pelsmaeker

Romero

Vitale

et al. 2018

J Virol

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Natural killer (NK) cells play an important role in the host response against viral infections and cancer development. They are able to kill virus-infected and tumor cells, and they produce different important cytokines that stimulate the antiviral and antitumor adaptive immune response, particularly interferon gamma. NK cells are of particular importance in herpesvirus infections, which is illustrated by systemic and life-threatening herpesvirus disease symptoms in patients with deficiencies in NK cell activity and by the myriad of reports describing herpesvirus NK cell evasion strategies. The latter is particularly obvious for cytomegaloviruses, but increasing evidence indicates that most, if not all, members of the herpesvirus family suppress NK cell activity to some extent. This review discusses the different NK cell evasion strategies described for herpesviruses and how this knowledge may translate to clinical applications.

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Human cytomegalovirus escapes immune recognition by NK cells through the downregulation of B7-H6 by the viral genes US18 and US20

Cited by 41 publications

References 44 publications

The integrated stress response promotes B7H6 expression

The integrated stress response promotes B7H6 expression

Tuning the Orchestra: HCMV vs. Innate Immunity

Herpesvirus Evasion of Natural Killer Cells

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