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 V gamma 9V delta 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 gamma delta-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 gamma 9V delta 2-T cells following antigenic stimulation. CD137(+) V gamma 9V delta 2-T cells displayed more potent antiviral activity against influenza virus than their CD137(-) counterparts in vitro and in Rag2(-/-) gamma c(-/-) mice. We further demonstrated that CD137 costimulation was essential for V gamma 9V delta 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 gamma 9V delta 2-T cell-based immunotherapy.