Uncompromised NK cell activation is essential for virus-specific CTL activity during acute influenza virus infection

Natural killer (NK) cells are indispensable components of both the innate and adaptive immune response. However,their precise roles in the cross-talk between innate and adaptive immunity during influenza virus infection remaincontroversial. By comparing NK cell dynamics and activity under a sub-lethal dose and high dose of influenza virusinfection, we showed that influenza virus PR8 directly infected NK cells during natural infection, which wasconsistent with our previous findings obtained from an in vitro investigation of human NK cells. The impairments incytotoxicity and IFN-γ production by spleen NK cells following high-dose infection were accompanied by decreasedvirus-specific killing mediated by cytotoxic T lymphocytes (CTLs). Importantly, the weakened CTL activity could bereversed by adoptive transfer of spleen NK cells harvested from low-dose-infected mice but not healthy donors.Taken together, our data provide direct evidence supporting the contribution of NK cells to antiviral T-cellresponses. This study also indicates that a novel NK-targeted immune evasion strategy is used by influenza virusto shrink both innate and adaptive immune responses.

Multi-platform omics analysis reveals molecular signature for COVID-19 pathogenesis,prognosis and drug target discovery

Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019(COVID-19)are particularly important,as there is still no effective strategy for severe COVID-19 patient treatment.Herein,we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19.Integrative analyses of these omics data revealed several potential therapeutic targets,such as ANXA1 and CLEC3B.Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients.Further,we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity.The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort,with AUC reached to 0.904 and 0.988,respectively.In conclusion,our omics data proposed not only potential therapeutic targets,but also biomarkers for understanding the pathogenesis of severe COVID-19.

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

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 to treat seasonal and avian influenza virus infections.However,one notable drawback ofγδ-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 Vγ9Vδ2-T cells following antigenic stimulation.CD137^(+)Vγ9Vδ2-T cells displayed more potent antiviral activity against influenza virus than their CD137−counterparts in vitro and in Rag2^(-/-)γc^(-/-)mice.We further demonstrated that CD137 costimulation was essential for Vγ9Vδ2-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 Vγ9Vδ2-T cell-based immunotherapy.