Human γδ T-Cells: From Surface Receptors to the Therapy of High-Risk Leukemias

gamma delta T lymphocytes are potent effector cells, capable of efficiently killing tumor and leukemia cells. Their activation is mediated by gamma delta T-cell receptor (TCR) and by activating receptors shared with NK cells (e.g., NKG2D and DNAM-1) gamma delta T-cell triggering occurs upon interaction with specific ligands, including phosphoantigens (for V gamma 9V delta 2 TCR), MICA-B and UL16 binding protein (for NKG2D), and PVR and Nectin-2 (for DNAM-1). They also respond to cytokines undergoing proliferation and release of cytokines/chemokines. Although at the genomic level gamma delta T-cells have the potential of an extraordinary TCR diversification, in tissues they display a restricted repertoire. Recent studies have identified various gamma delta TCR rearrangements following either hematopoietic stem cell transplantation (HSCT) or cytomegalovirus infection, accounting for their adaptive potential. In humans, peripheral blood gamma delta T-cells are primarily composed of V gamma 9V delta 2 chains, while a minor proportion express V delta 1. They do not recognize antigens in the context of MHC molecules, thus bypassing tumor escape based on MHC class I downregulation. In view of their potent antileukemia activity and absence of any relevant graft-versus-host disease-inducing effect, gamma delta T-cells may play an important role in the successful clinical outcome of patients undergoing HLA-haploidentical HSCT depleted of TCR alpha beta T/CD19(+) B lymphocytes to cure high-risk acute leukemias. In this setting, high numbers of both gamma delta T-cells (V delta 1 and V delta 2) and NK cells are infused together with CD34(+) HSC and may contribute to rapid control of infections and leukemia relapse. Notably, zoledronic acid potentiates the cytolytic activity of gamma delta T-cells in vitro and its infusion in patients strongly promotes.d T-cell differentiation and cytolytic activity; thus, treatment with this agent may contribute to further improve the patient clinical outcome after HLA-haploidentical HSCT depleted of TCR alpha beta T/CD19(+) B lymphocytes.