Gamma delta (gd) T cells are the prototype of ‘unconventional’ T cells and represent a relatively small subset of T cells defined by their expression of heterodimeric T-cell receptors (TCRs) composed of g and d chains. This sets them apart from the classical and much better known CD4+ helper T cells and CD8+ cytotoxic T cells that are defined by ab TCRs. Like these cells they are mostly thymus dependent.
Tissue-associated gd T cell populations
gd T cells often show tissue-specific localisation of oligoclonal subpopulations sharing the same TCR chains. For instance, human peripheral blood gd T cells are largely Vg9/Vd2+ and murine skin gd T cells, so-called dendritic epidermal T cells (DETCs), are largely Vg5/Vd1+. It is also noteworthy that gd T cells are highly abundant in ruminants and enriched in epithelia.
Recognition of target cells by gd T cells
The majority of gd T cells are activated in an MHC-independent manner, in striking contrast to MHC-restricted ab T cells. The antigens recognised by most gd T cells are still unknown. A small proportion of murine gd T cells (<1%) bind the MHC-I-related proteins T10 and T22 that are expressed by highly activated cells. Human Vg9/Vd2+ T cells show TCR-dependent activation by certain low molecular weight phosphorylated molecules such as the microbial metabolite HMB-PP that is produced by most bacterial and some protozoan pathogens, and the cellular isoprenoid precursor IPP. Most gd T cells also recognise stress-induced surface markers on infected cells and tumours through NK receptors such as NKG2D. Some reports suggest recognition of virus proteins by certain gd T cells.
gd T cell-mediated immune responses
In response to their rapid recognition of infected or stressed cells, gd T cells display broad functional plasticity; e.g. by production of cytokines (IFN-g, TNF-a, 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. Especially human Vg9/Vd2+ T cells are also capable of presenting exogenous antigen on MHC-II molecules to helper T cells or cross-presenting it on MHC-I molecules to cytotoxic T cells. These potentials permit gd T cells to orchestrate immune responses in inflammation, tumour surveillance, infectious disease, and autoimmunity.
gd T cells for immunotherapy
Their non-MHC-restricted cytotoxicity toward a broad range of target cells have established gd T cells as promising tools for immunotherapy against a variety of solid and haematological cancers. This can be achieved by systemic activation of human gd T cells by intravenous injection of aminobisphosphonates (e.g. zoledronic acid) or synthetic HMB-PP analogues (e.g. Phosphostim). gd T cells can also be recovered from blood, expanded ex vivo and reinfused into patients at a later time point. The immunotherapeutic potential of gd T cells is being tested in a number of clinical trials.
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