Repertoire development and the control of cytotoxic/effector function in human gammadelta T cells

Abstract

T cells develop into two major populations distinguished by their T cell receptor (TCR) chains. Cells with the alphabeta TCR generally express CD4 or CD8 lineage markers and mostly fall into helper or cytotoxic/effector subsets. Cells expressing the alternate gammadelta TCR in humans generally do not express lineage markers, do not require MHC for antigen presentation, and recognize nonpeptidic antigens. We are interested in the dominant Vgamma2Vdelta2+ T cell subset in human peripheral blood and the control of effector function in this population. We review the literature on gammadelta T cell generation and repertoire selection, along with recent work on CD56 expression and defining a cytotoxic/effector lineage within the phosphoantigen-reactive Vgamma2Vdelta2 cells. A unique mechanism for MHC-independent repertoire selection is linked to the control of effector function that is vital to the role for gammadelta T cells in tumor surveillance. Better understanding of these mechanisms will improve our ability to exploit this population for tumor immunotherapy.

Figure 1

T Cell Development. γ δ T cells most often arise from the CD4−CD8− (double negative, DN) stages of thymocyte development as a result of successful rearrangements of both the γ and δ TCR chains. Little, if any, proliferation occurs between these steps, thus limiting diversity. Signals delivered in trans from the CD4+CD8+ (double positive, DP) population is crucial for the development of effector functions in γ δ cells. Figure adapted from Hayday and Pennington [18].

Figure 2

Human Vγ2Vδ2 T cells respond to stimulatory phosphoantigens produced during bacterial or mammalian isoprenoid synthesis. Isoprenoid synthesis in many prokaryotes and protists produces the intermediate (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) from pyruvate and glyceraldehyde 3-phosphate via the erythritol 4 phosphate pathway. Eukaryotes use the mevalonate pathway that produces isoprenoids and colesterol. HMBPP and IPP are phosphoantigens; HMBPP is unique to the erythritol 4 phosphate pathway while IPP is produced in both pathways. Phosphoantigens stimulate cytokine secretion and cytotoxicity in human Vγ2Vδ2 T cells. Statins block the eukaryotic pathway prior to mevalonate synthesis, and decrease the production of IPP. Bisphosphonates are a class of drugs that inhibit farnesyl pyrophosphate synthase and cause the accumulation of IPP in mammalian cells. When mammalian cells of myeloid origin and some tumor cells are treated with bisphosphonate, they are more stimulatory for Vγ2Vδ2 T cells due to increased IPP production.