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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.