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

Abstract

γδ T lymphocytes are potent effector cells, capable of efficiently killing tumor and leukemia cells. Their activation is mediated by γδ T-cell receptor (TCR) and by activating receptors shared with NK cells (e.g., NKG2D and DNAM-1). γδ T-cell triggering occurs upon interaction with specific ligands, including phosphoantigens (for Vγ9Vδ2 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 γδ T-cells have the potential of an extraordinary TCR diversification, in tissues they display a restricted repertoire. Recent studies have identified various γδ TCR rearrangements following either hematopoietic stem cell transplantation (HSCT) or cytomegalovirus infection, accounting for their "adaptive" potential. In humans, peripheral blood γδ T-cells are primarily composed of Vγ9Vδ2 chains, while a minor proportion express Vδ1. 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, γδ T-cells may play an important role in the successful clinical outcome of patients undergoing HLA-haploidentical HSCT depleted of TCR αβ T/CD19+ B lymphocytes to cure high-risk acute leukemias. In this setting, high numbers of both γδ T-cells (Vδ1 and Vδ2) 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 γδ T-cells in vitro and its infusion in patients strongly promotes γδ 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 αβ T/CD19+ B lymphocytes.

• Authors: Vito Pistoia, Nicola Tumino, Paola Vacca, Irene Veneziani, Alessandro Moretta, Franco Locatelli, Lorenzo Moretta
• Journal: Frontiers in immunology (Front Immunol) Vol. 9 Pg. 984 ( 2018) ISSN: 1664-3224 [Print] Switzerland
• PMID: 29867961 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Receptors, Antigen, T-Cell, alpha-beta

Topics

• Animals
• B-Lymphocytes (immunology)
• Cytomegalovirus Infections
• Genes, MHC Class I
• Hematopoietic Stem Cell Transplantation
• Humans
• Intraepithelial Lymphocytes (immunology, metabolism)
• Killer Cells, Natural (immunology)
• Leukemia (immunology, therapy)
• Mice
• Receptors, Antigen, T-Cell, alpha-beta (genetics)