CD137 costimulation enhances the antiviral activity of Vγ9Vδ2-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 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.

Function of γδ T cells in tumor immunology and their application to cancer therapy

“…CD137 (4-1BB) can enhance Vγ9Vδ2 T-cell function following influenza or Listeria infection. Thus, CD137 may also be involved in the antitumor function of γδ T cells 78 , 79 .…”

NKG2D as a Cell Surface Marker on γδ-T Cells for Predicting Pregnancy Outcomes in Patients With Unexplained Repeated Implantation Failure

“…In this context, γδ-T cells, a group of unconventional T cells that express the T cell receptor containing a γ and δ chain, display an important role due to their early and rapid response against cellular stress and infections in an major histocompatibility complex (MHC)-independent manner ( 6 ). Although γδ-T cells represent a minor population of T lymphocytes (1–10%) ( 7 , 8 ), they exhibit multiple immunological functions, such as anti-viral infection, inflammation regulation, tissue homeostasis, and even in maintaining successful pregnancy ( 9 – 13 ). In the early 1990s, some studies suggested that peripheral γδ-T cells play an important role in decreasing natural killer activity through secreting anti-inflammatory cytokines during the whole pregnancy process ( 14 , 15 ).…”

Role of hormones in the pregnancy and sex‐specific outcomes to infections with respiratory viruses*

“…221,226,227 This subset also strongly relies on CD137 co-stimulation for ideal effector function and expresses high levels of CD69 activation marker in the context of influenza infection. [227][228][229] In other respiratory viral infections, γδT cells also form a fundamental portion of the antiviral innate immune response. During RSV infection, IL-17 expression is impaired in neonates and Vγ4+ γδ T cells adopt an IFN-γ+, proinflammatory cytokine secretome.…”