Transcript Document
CATEGORY: CELLS GAMMA DELTA (gd) T CELLS Gamma Delta (gd) T Cells Matthias Eberl, Cardiff University, UK Adrian Hayday, King’s College London, UK 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 MHCrestricted 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. RECOGNITION Self ligands Non-self ligands IPP HMB-PP T10, T22 TCR virus proteins gd NKG2D ligands NKG2D TLR TLR ligands RESPONSE Cytokine production Inflammation B cell help Chemokine production Epithelial growth DC maturation Cytotoxicity Wound healing Antigen presentation 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. © The copyright for this work resides with the author 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.