Gamma delta (γδ) T cells are the prototype of ‘unconventional’ T cells and represent a relatively small subset of T cells in peripheral blood. They are defined by expression of heterodimeric T-cell receptors (TCRs) composed of γ and δ chains. This sets them apart from the classical and much better known CD4+ helper T cells and CD8+ cytotoxic T cells that express αβ TCRs. The mechanism of (thymic) selection of γδ T cells is still largely unknown.

Tissue-associated γδ T cell populations

γδ T cells often show tissue-specific localisation of oligoclonal subpopulations sharing the same TCR chains. For instance, human peripheral blood γδ T cells are largely Vγ9/Vδ2+, and murine skin γδ T cells, so-called dendritic epidermal T cells (DETCs), are largely Vγ5/Vδ1+. In general, γδ T cells are enriched in epithelial and mucosal tissues where they are thought to serve as the first line of defense against pathogenic challenge.

Recognition of target cells by γδ T cells

The majority of γδ T cells are activated in an MHC-independent manner, in striking contrast to MHC-restricted αβ T cells. The antigens recognised by most γδ T cells are still unknown. A small proportion of murine γδ T cells (<1%) bind the MHC-I-related proteins T10 and T22 that are expressed by highly activated cells. Human Vγ9/Vδ2+T cells show TCR-dependent activation by certain phosphorylated metabolites such as microbial HMB-PP or eukaryotic isoprenoid precursor IPP. Due to metabolic dysregulation IPP is often accumulated by cancer cells. Some γδ T cells also recognise markers of cellular stress, resulting from infection or tumorigenesis. Stress surveillance performed by γδ T cells is thought to depend not only on their TCRs but also on co-stimulatory signals from, for instance, NK-type receptors. Finally, γδ TCRs have been shown to recognise lipid antigens presented by CD1 molecules, in particular CD1d.

γδ T cell-mediated immune responses

γδ T cells display broad functional plasticity following recognition of infected/transformed cells by production of cytokines (IFN-γ, TNF-α, IL-17) and chemokines (RANTES, IP-10, lymphotactin), cytolysis of infected or transformed target cells (perforin, granzymes, TRAIL), and interaction with other cells including epithelial cells, monocytes, dendritic cells, neutrophils, and B cells. In particular, human Vγ9/Vδ2+ T cells are capable of serving as professional antigen presenting cells.

Certain infections (e.g. human cytomegalovirus) have been shown to drive clonal expansion of peripheral γδ T cells bearing person-specific TCRs, indicating the adaptive nature of γδ T cell-mediated immune response.

γδ T cells for immunotherapy

γδ T cells are capable of recognising and lysing diverse cancers in an MHC-unrestricted manner, highlighting their potential for pan-population immunotherapy, in contrast to MHC-restricted αβ T-cell mediated immunotherapy. Past clinical trials, which focused on Vγ9/Vδ2+ T cells expanded using phosphorylated metabolites, showed an overall good safety profile but the clinical efficacy was generally underwhelming. The potential of γδ T cells for pan-population immunotherapy will be evaluated in upcoming clinical trials using different subsets of γδ T cells or specific γδ TCRs.

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This article was updated in 2022