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CD137 costimulation enhances the antiviral activity of V?9V?2-T cells against influenza virus.

ABSTRACT: Influenza epidemics and pandemics are constant threats to global public health. Although strategies including vaccines and antiviral drugs have achieved great advances in controlling influenza virus infection, the efficacy of these strategies is limited by the highly frequent mutations in the viral genome and the emergence of drug-resistant strains. Our previous study indicated that boosting the immunity of human V?9V?2-T cells with the phosphoantigen pamidronate could be a therapeutic strategy to treat seasonal and avian influenza virus infections. However, one notable drawback of ??-T cell-based immunotherapy is the rapid exhaustion of proliferation and effector responses due to repeated treatments with phosphoantigens. Here, we found that the expression of CD137 was inducible in V?9V?2-T cells following antigenic stimulation. CD137+ V?9V?2-T cells displayed more potent antiviral activity against influenza virus than their CD137- counterparts in vitro and in Rag2-/- ?c-/- mice. We further demonstrated that CD137 costimulation was essential for V?9V?2-T cell activation, proliferation, survival and effector functions. In humanized mice reconstituted with human peripheral blood mononuclear cells, CD137 costimulation with a recombinant human CD137L protein boosted the therapeutic effects of pamidronate against influenza virus. Our study provides a novel strategy of targeting CD137 to improve the efficacy of V?9V?2-T cell-based immunotherapy.

SUBMITTER: Pei Y

PROVIDER: S-EPMC7266814 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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CD137 costimulation enhances the antiviral activity of Vγ9Vδ2-T cells against influenza virus.

Pei Yujun Y Wen Kun K Xiang Zheng Z Huang Chunyu C Wang Xiwei X Mu Xiaofeng X Wen Liyan L Liu Yinping Y Tu Wenwei W

Signal transduction and targeted therapy 20200603 1

Influenza epidemics and pandemics are constant threats to global public health. Although strategies including vaccines and antiviral drugs have achieved great advances in controlling influenza virus infection, the efficacy of these strategies is limited by the highly frequent mutations in the viral genome and the emergence of drug-resistant strains. Our previous study indicated that boosting the immunity of human Vγ9Vδ2-T cells with the phosphoantigen pamidronate could be a therapeutic strategy ...[more]

PMID: 32488072

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Project description:BackgroundInfluenza represents a serious public health concern. The emergence of resistance to anti-influenza drugs underlines the need to develop new drugs. This study aimed to evaluate the anti-influenza viral activity and possible mechanisms of 12 phenanthrenes from the medicinal plant Bletilla striata (Orchidaceae family).MethodsTwelve phenanthrenes were isolated and identified from B. striata. Influenza virus A/Sydney/5/97 (H3N2) propagated in embryonated chicken eggs was used. Phenanthrenes mixed with the virus were incubated at 37 °C for 1 h and then inoculated into 9-day-old embryonated chicken eggs via the allantoic route to survey the antiviral activity in vivo. A (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS)-based assay was performed to evaluate the reduction of cytopathic effect induced by H3N2 on Madin-Darby canine kidney (MDCK) cells. The hemagglutination inhibition assay was used to study the blockage of virus receptors by the phenanthrenes, and the neuraminidase (NA) inhibition assay to evaluate the effects of the release of virus. The synthesis of influenza viral matrix protein mRNA in response to compound treatment was measured by real-time polymerase chain reaction.ResultsThis study showed that phenanthrenes 1, 2, 3, 4, 6, 9, 10, 11, and 12 significantly inhibited the viruses in vivo, with inhibition rates of 20.7, 79.3, 17.2, 34.5, 34.5, 34.5, 44.8, 75.9, and 34.5%, respectively. In MDCK models, the phenanthrenes did not show significant antiviral activity when administered as pretreatment, while phenanthrenes 2, 3, 4, 6, 7 10, and 11 exhibited inhibitory activities as simultaneous treatment with 50% inhibition concentration (IC50) ranging from 14.6 ± 2.4 to 43.3 ± 5.3 μM. The IC50 ranged from 18.4 ± 3.1 to 42.3 ± 3.9 μM in the post-treatment assays. Compounds 1, 3, 4, 6, 10, and 11 exhibited an inhibitory effect on NA; and compounds 2, 3, 4 6, 7, 10, and 11 resulted in the reduced transcription of virus matrix protein mRNA. However, no compound could inhibit hemagglutination by the influenza virus.ConclusionPhenanthrenes from B. striata had strong anti-influenza viral activity in both embryonated eggs and MDCK models, and diphenanthrenes seemed to have stronger inhibition activity compared with monophenanthrenes.

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CD137 costimulation enhances the antiviral activity of V?9V?2-T cells against influenza virus.

Publications

CD137 costimulation enhances the antiviral activity of Vγ9Vδ2-T cells against influenza virus.

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