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.

Keywords: BCG; COVID-19; antiviral; gamma delta T cell; innate immunity; trained immunity; vaccine; virus.

Figure 1

The multifactorial capacity for the γδ T-cell to interact with viruses and virally infected targets. Numerous pathways are crucial in the γδ T-cell mediated antiviral response. γδ T-cells are capable of rapidly recognizing virally infected cells. This can occur via the detection of isopentenyl pyrophosphate (IPP) by the T-cell receptor (TCR), via recognition of stress-induced molecules by NKG2D, or via the recognition of viral molecules and PAMPs by NK-type receptors and TLR, respectively. γδ T-cells have numerous mechanisms to directly combat viral infection. Direct antiviral mechanisms are mediated by cytolytic molecules, such as perforin and granzyme B, to induce cytolysis and by the expression of death receptors, including FasL and TRAIL, to induce apoptosis. γδ T-cells also have several indirect mechanisms capable of combatting viral infection. Indirect antiviral mechanisms are mediated by cytokines, such as IFNγ and TNF, by the expression of MHC-II allowing them to act as APC to direct the adaptive immune response and via expression of CD16 to trigger antibody-dependent cellular cytotoxicity. Together these actions make the γδ T-cell a crucial component in the immune response to viruses.