By Binding CD80 and CD86, the Vaccinia Virus M2 Protein Blocks Their Interactions with both CD28 and CTLA4 and Potentiates CD80 Binding to PD-L1

Kleinpeter, Patricia; Remy-Ziller, Christelle; Winter, Eline; Gantzer, Murielle; Nourtier, Virginie; Kempf, Juliette; Hortelano, Julie; Schmitt, D; Schultz, Huguette; Geist, Michel; Brua, Catherine; Hoffmann, Chantal; Schlesinger, Yasmin; Villeval, Dominique; Thioudellet, Christine; Erbs, Philippe; Foloppe, Johann; Silvestre, Nathalie; Fend, Laetitia; Quéméneur, Éric; Marchand, Jean-Baptiste

doi:10.1128/jvi.00207-19

Cited by 18 publications

(22 citation statements)

References 36 publications

(49 reference statements)

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“…Various strains of VACV have been used as vaccines or vectors to treat a number of infections, as well as cancers (44,45). A recent study reported that the M2 protein encoded by the VACV Copenhagen strain can also bind B7 ligands (46), and notably, M2 is absent from certain attenuated VACV strains, for example, modified vaccinia virus Ankara and its derivative Acam3000. Taken together, these findings have implications for the design of poxvirus-based vectors where deletion of the M2 ORF could potentially improve T cell responses.…”

Section: Discussionmentioning

confidence: 99%

Cowpox virus encodes a protein that binds B7.1 and B7.2 and subverts T cell costimulation

Wang

Piersma

Elliott

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Costimulation is required for optimal T cell activation, yet it is unclear whether poxviruses dedicatedly subvert costimulation during infection. Here, we report that the secreted M2 protein encoded by cowpox virus (CPXV) specifically interacts with human and murine B7.1 (CD80) and B7.2 (CD86). We also show that M2 competes with CD28 and CTLA4 for binding to cell surface B7 ligands, with stronger efficacy against CD28. Functionally, recombinant M2 and culture supernatants from wild-type (WT) but not M2-deficient (∆M2) CPXV-infected cells can potently suppress B7 ligand-mediated T cell proliferation and interleukin-2 (IL-2) production. Furthermore, we observed increased antiviral CD4 and CD8 T cell responses in C57BL/6 mice challenged by ∆M2 CPXV compared with WT virus. These differences in immune responses to ∆M2 and WT CPXV were not observed in CD28-deficient mice. Taken together, our findings define a mechanism of viral sabotage of T cell activation that highlights the role of CD28 costimulation in host defense against poxvirus infections.

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Section: Discussionmentioning

confidence: 99%

Cowpox virus encodes a protein that binds B7.1 and B7.2 and subverts T cell costimulation

Wang

Piersma

Elliott

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Treg cells help to confine the antiviral defense and to prevent immunopathology during virus infections (Veiga-Parga et al, 2013). Taken together, viruses can reprogram DC function in antiviral immune responses by tipping the balance between co-inhibitory and co-stimulatory signals as shown for murine cytomegalovirus (Loewendorf et al, 2004; Benedict et al, 2008) and vaccinia virus (Kleinpeter et al, 2019).…”

Section: Function Of Pd-l1 During Acute Virus Infectionsmentioning

confidence: 97%

The PD-1/PD-L1 Axis and Virus Infections: A Delicate Balance

Schönrich

Raftery

2019

Front. Cell. Infect. Microbiol.

221

203

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Programmed cell death protein (PD-1) and its ligands play a fundamental role in the evasion of tumor cells from antitumor immunity. Less well appreciated is the fact that the PD-1/PD-L1 axis also regulates antiviral immune responses and is therefore modulated by a number of viruses. Upregulation of PD-1 and its ligands PD-L1 and PD-L2 is observed during acute virus infection and after infection with persistent viruses including important human pathogens such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV). Experimental evidence suggests that insufficient signaling through the PD-1 pathway promotes immunopathology during acute infection by exaggerating primary T cell responses. If chronic infection is established, however, high levels of PD-1 expression can have unfavorable immunological consequences. Exhaustion and suppression of antiviral immune responses can result in viral immune evasion. The role of the PD-1/PD-L1 axis during viral infections is further complicated by evidence that PD-L1 also mediates inflammatory effects in the acute phase of an immune response. In this review, we discuss the intricate interplay between viruses and the PD-1/PD-L1 axis.

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“…However, CD80 expression increased significantly on DCs co-cultured with oleandrin-pretreated MDA-MB-231 cells. CD80 along with CD86 that are markers of active DCs bind to CD28 on T cells and act as a costimulatory signal for T cell activation 38 . Moreover, oleandrin treatment decreased IL-10 expression but increased IL-2 and IFN-γ secretion.…”

Section: Discussionmentioning

confidence: 99%

Oleandrin, a cardiac glycoside, induces immunogenic cell death via the PERK/elF2α/ATF4/CHOP pathway in breast cancer

Zheng

Shi

et al. 2021

Cell Death Dis

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Chemotherapeutic agents have been linked to immunogenic cell death (ICD) induction that is capable of augmenting anti-tumor immune surveillance. The cardiac glycoside oleandrin, which inhibits Na+/K+-ATPase pump (NKP), has been shown to suppress breast cancer growth via inducing apoptosis. In the present study, we showed that oleandrin treatment triggered breast cancer cell ICD by inducing calreticulin (CRT) exposure on cell surface and the release of high-mobility group protein B1 (HMGB1), heat shock protein 70/90 (HSP70/90), and adenosine triphosphate (ATP). The maturation and activation of dendritic cells (DCs) were increased by co-culturing with the oleandrin-treated cancer cells, which subsequently enhanced CD8+ T cell cytotoxicity. Murine breast cancer cell line EMT6 was engrafted into BALB/c mice, and tumor-bearing mice were administered with oleandrin intraperitoneally every day. Oleandrin inhibited tumor growth and increased tumor infiltrating lymphocytes including DCs and T cells. Furthermore, the differential mRNA expression incurred by oleandrin was investigated by mRNA sequencing and subsequently confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Mechanistically, oleandrin induced endoplasmic reticulum (ER) stress-associated, caspase-independent ICD mainly through PERK/elF2α/ATF4/CHOP pathway. Pharmacological and genetic inhibition of protein kinase R-like ER kinase (PERK) suppressed oleandrin-triggered ICD. Taken together, our findings showed that oleandrin triggered ER stress and induced ICD-mediated immune destruction of breast cancer cells. Oleandrin combined with immune checkpoint inhibitors might improve the efficacy of immunotherapy.

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By Binding CD80 and CD86, the Vaccinia Virus M2 Protein Blocks Their Interactions with both CD28 and CTLA4 and Potentiates CD80 Binding to PD-L1

Cited by 18 publications

References 36 publications

Cowpox virus encodes a protein that binds B7.1 and B7.2 and subverts T cell costimulation

Cowpox virus encodes a protein that binds B7.1 and B7.2 and subverts T cell costimulation

The PD-1/PD-L1 Axis and Virus Infections: A Delicate Balance

Oleandrin, a cardiac glycoside, induces immunogenic cell death via the PERK/elF2α/ATF4/CHOP pathway in breast cancer

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