How to Train Your Dragon: Harnessing Gamma Delta T Cells Antiviral Functions and Trained Immunity in a Pandemic Era

Abstract

The emergence of viruses with pandemic potential such as the SARS-CoV-2 coronavirus causing COVID-19 poses a global health challenge. There is remarkable progress in vaccine technology in response to this threat, but their design often overlooks the innate arm of immunity. Gamma Delta (γδ) T cells are a subset of T cells with unique features that gives them a key role in the innate immune response to a variety of homeostatic alterations, from cancer to microbial infections. In the context of viral infection, a growing body of evidence shows that γδ T cells are particularly equipped for early virus detection, which triggers their subsequent activation, expansion and the fast deployment of antiviral functions such as direct cytotoxic pathways, secretion of cytokines, recruitment and activation of other immune cells and mobilization of a trained immunity memory program. As such, γδ T cells represent an attractive target to stimulate for a rapid and effective resolution of viral infections. Here, we review the known aspects of γδ T cells that make them crucial component of the immune response to viruses, and the ways that their antiviral potential can be harnessed to prevent or treat viral infection.

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“…In addition to TLRs and TCRs gd T cells express other receptors, several of which are likely to be important in the recognition of viral infection, including NK type receptors (NKRs), DNAX Accessory Molecule 1 (DNAM1), and the Natural Cytotoxicity receptors (NCRs) NKp30, NK44 and NKp46. This review focuses on the NKR natural killer group 2-member D (NKG2D) only, as other NKRs have been recently reviewed by Caron et al (69). NKG2D is an activating C-type lectin originally found on Natural Killer cells, but also highly expressed on both Vd1 and Vd2 T cells.…”

“…γδ T cells are involved in the first line of defense to a number of diseases, including cancer, bacterial infections, and viral infections. Studies have demonstrated their rapid activation and cytotoxicity to various viruses, including cytomegalovirus (CMV) ( 52 , 53 ), influenza A virus ( 54 – 56 ), human immunodeficiency virus (HIV) ( 57 – 59 ), hepatitis B and C viruses (HBV and HCV) ( 60 – 62 ), Epstein Bar Virus (EBV) ( 63 ) and severe acute respiratory syndrome (SARS) virus ( 64 ), as reviewed by others ( 50 , 51 , 65 – 69 ). Additionally, γδ TCR knockout mice show an increase in viral titer or reduced survival when infected with West Nile virus or vaccinia virus ( 70 , 71 ).…”

“…This review focuses on the NKR natural killer group 2-member D (NKG2D) only, as other NKRs have been recently reviewed by Caron et al. ( 69 ). NKG2D is an activating C-type lectin originally found on Natural Killer cells, but also highly expressed on both Vδ1 and Vδ2 T cells.…”

“…Once induced, their interaction with NKG2D on γδ T cells can assist activation and produce a powerful cytotoxic response. It is currently unknown the extent to which SARS-CoV-2 infection upregulates NKG2D ligands, however many ligands have been found to be upregulated on virally infected cells ( 69 ). For example, CMV infected cells have been shown to upregulate MICA and ULBP1-3 ( 87 ); EBV infected cells can upregulate MICA, MICB and ULBP4 ( 88 , 89 ); and cells infected with either influenza A or Sendai virus can upregulate MICB ( 90 ).…”

“…γδ T cells can produce proinflammatory cytokines in response to viral recognition, including IFN-γ and TNF-α ( 98 ). These two cytokines trigger a multitude of pathways in target cells that can ultimately lead to the inhibition of viruses at all stages of their replication: viral entry, viral protein synthesis, viral assembly, and viral release, as recently reviewed ( 69 ). Many γδ T cells produce multiple pro-inflammatory cytokines simultaneously, which have synergistic effects on virally infected cells, and are particularly effective for viruses that have evolved escape mechanisms from one or many of the cytokine-induced pathways.…”