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 Vγ9Vδ2-T cells with the phosphoantigen pamidronate could be a therapeutic strategy to treat seasonal and avian influenza virus infections. However, one notable drawback of γδ-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.
Highlights
We demonstrated that phosphoantigen-activated Vγ9Vδ2-T cells have antiviral activities against human and avian influenza viruses mediated by killing virus-infected monocytederived macrophages (MDMs), inhibiting virus replication, and promoting the production of virus-specific antibodies.[16,17,18,19,20]
Using a recombinant human SA-hCD137L protein containing the extracellular domains of human CD137L fused to a core streptavidin (SA) molecule, we demonstrated that SAhCD137L is an efficient adjuvant for PAM therapy for influenza virus infection that functions by improving the antiviral activity of human Vγ9Vδ2-T cells in humanized mice
CD137L expression was rapidly upregulated in MDMs, and 25.7 ± 4.3% of the MDMs became CD137L+ cells after 24 h of influenza virus infection (Fig. 1d)
Summary
Influenza is an acute respiratory virus infection that continues to pose epidemic, zoonotic and pandemic threats to global human health with significant morbidity and mortality.[1,2] strategies including vaccines and antiviral drugs have achieved great advances in controlling influenza virus infection, the efficacy of these strategies is still limited by the highly frequent mutations in the viral genome and emergence of drug-resistant strains.[3,4,5] A strategy to boost host innate immunity was recently thought to have obvious advantages in controlling influenza infection without the risks of viral mutation and antiviral resistance.[6,7,8] γδ-T cells, as innate-like T lymphocytes, represent a minor but crucial population in the immune system.[9,10,11,12] Most γδ-T cells in the peripheral blood and lymphoid organs of healthy human adults are Vγ9Vδ2-T cells. Vγ9Vδ2-T cells can be activated in an HLA-unrestricted manner by small nonpeptidic phosphoantigens, which are metabolites of isoprenoid biosynthesis pathways.[13]. Pharmacological compounds, such as the aminobisphosphonates pamidronate (PAM) and zoledronate, which are commonly used for the treatment of osteoporosis and Paget’s disease, can induce the activation and expansion of human Vγ9Vδ2-T cells.[11,14,15] Previously, we demonstrated that phosphoantigen-activated Vγ9Vδ2-T cells have antiviral activities against human and avian influenza viruses mediated by killing virus-infected monocytederived macrophages (MDMs), inhibiting virus replication, and promoting the production of virus-specific antibodies.[16,17,18,19,20] Recently, we further reported that PAM can control influenza diseases by expanding the Vγ9Vδ2-T cell population in humanized mice.[21,22] the application of PAM for the treatment of influenza is limited by the rapid exhaustion of the proliferation and effector responses of Vγ9Vδ2-T cells resulting from repeated treatments with the phosphoantigens. The underlying mechanisms of this exhaustion are still not clear, the suboptimal stimulation or lack of optimal costimulation may explain it
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