Gamma/delta (?d) T-cells are a small subset of T-lymphocytes in the peripheral circulation but constitute a major T-cell population at other anatomical localizations such as the epithelial tissues. In contrast to conventional a/ß T-cells, the available number of germline genes coding for T-cell receptor (TCR) variable elements of ?d T-cells is very small. Moreover, there is a prefential localization of ?d T-cells expressing given Vgamma and Vdelta genes in certain tissues. In humans, ?d T-cells expressing the Vg9Vd2-encoded TCR account for anywhere between 50 and >95% of peripheral blood ?d T-cells, whereas cells expressing non-Vd2 genes dominate in mucosal tissues. In mice, there is an ordered appearance of ?d T-cell „waves“ during embryonic development, resulting in preferential localization of ?d T-cells expressing distinct VgammaVdelta genes in the skin, the reproductive organs, or gut epithelia. The major function of ?d T-cells resides in local immunosurveillance and immune defense against infection and malignancy. This is supported by the identification of ligands that are selectively recognized by the ?d TCR. As an example, human Vgamma9Vdelta2 T-cells recognize phosphorylated metabolites („phosphoantigens“) that are secreted by many pathogens but can also be overproduced by tumor cells, providing a basis for a role of these ?d T-cells in both anti-infective and anti-tumor immunity. Similarly, the recognition of endothelial protein C receptor by human non-Vdelta2 ?d T-cells has recently been identified to provide a link for the role for such ?d T-cells in immunity against epithelial tumor cells and cytomegalovirus-infected endothelial cells. In addition to „classical“ functions such as cytokine production and cytotoxicity, recent studies suggest that subsets of ?d T-cells can exert additional functions such as regulatory activity and – quite surpisingly – „professional“ antigen-presenting capacity. It is currently not well known how this tremendous extent of functional plasticity is regulated and what is the extent of ?d TCR ligand diversity. Due to their non-MHC-restricted recognition of unusual stress-associated ligands, ?d T-cells have raised great interest as to their potential translational application in cell-based immunotherapy. Topics of interest for this research focus include (but are not restricted to):
• Identification of ligands for human and murine ?d T-cell receptors
• Presentation pathways and presenting molecules for unusual ?d T-cell ligands
• Activation requirements (including co-stimulation) for ?d T-cells
• Role of ?d T-cell subsets in tumor and infection immunity
• Regulatory activity of ?d T-cells and cross-talk with other immune cells
• Antigen-presenting function of ?d T-cell subsets
• Cooperation between ?d T cells and antibodies
• Protocols for large-scale expansion of human ?d T-cells
• Designing clinical studies with ?d T-cells
Gamma/delta (?d) T-cells are a small subset of T-lymphocytes in the peripheral circulation but constitute a major T-cell population at other anatomical localizations such as the epithelial tissues. In contrast to conventional a/ß T-cells, the available number of germline genes coding for T-cell receptor (TCR) variable elements of ?d T-cells is very small. Moreover, there is a prefential localization of ?d T-cells expressing given Vgamma and Vdelta genes in certain tissues. In humans, ?d T-cells expressing the Vg9Vd2-encoded TCR account for anywhere between 50 and >95% of peripheral blood ?d T-cells, whereas cells expressing non-Vd2 genes dominate in mucosal tissues. In mice, there is an ordered appearance of ?d T-cell „waves“ during embryonic development, resulting in preferential localization of ?d T-cells expressing distinct VgammaVdelta genes in the skin, the reproductive organs, or gut epithelia. The major function of ?d T-cells resides in local immunosurveillance and immune defense against infection and malignancy. This is supported by the identification of ligands that are selectively recognized by the ?d TCR. As an example, human Vgamma9Vdelta2 T-cells recognize phosphorylated metabolites („phosphoantigens“) that are secreted by many pathogens but can also be overproduced by tumor cells, providing a basis for a role of these ?d T-cells in both anti-infective and anti-tumor immunity. Similarly, the recognition of endothelial protein C receptor by human non-Vdelta2 ?d T-cells has recently been identified to provide a link for the role for such ?d T-cells in immunity against epithelial tumor cells and cytomegalovirus-infected endothelial cells. In addition to „classical“ functions such as cytokine production and cytotoxicity, recent studies suggest that subsets of ?d T-cells can exert additional functions such as regulatory activity and – quite surpisingly – „professional“ antigen-presenting capacity. It is currently not well known how this tremendous extent of functional plasticity is regulated and what is the extent of ?d TCR ligand diversity. Due to their non-MHC-restricted recognition of unusual stress-associated ligands, ?d T-cells have raised great interest as to their potential translational application in cell-based immunotherapy. Topics of interest for this research focus include (but are not restricted to):
• Identification of ligands for human and murine ?d T-cell receptors
• Presentation pathways and presenting molecules for unusual ?d T-cell ligands
• Activation requirements (including co-stimulation) for ?d T-cells
• Role of ?d T-cell subsets in tumor and infection immunity
• Regulatory activity of ?d T-cells and cross-talk with other immune cells
• Antigen-presenting function of ?d T-cell subsets
• Cooperation between ?d T cells and antibodies
• Protocols for large-scale expansion of human ?d T-cells
• Designing clinical studies with ?d T-cells
