Unraveling the Mystery of γδ T Cell Immune Recognition

A research team has reported the immune recognition mechanism of γδ T cells, which brings new prospects for immunotherapy and vaccine development, among others. Here, Creative Biolabs introduces relevant recent research advances.

Mechanism of Antigen Recognition by γδ T Cells

The mechanisms of antigen recognition by γδ T cells are multifaceted and involve a combination of TCR-mediated signaling, costimulatory interactions, and integration with other immune pathways.

• TCR-mediated signaling: The TCR on γδ T cells plays a central role in antigen recognition. Upon binding to cognate antigens, the TCR initiates a signaling cascade that culminates in the activation of γδ T cells.
• Co-stimulatory interactions: These interactions provide secondary signals that enhance the activation and effector functions of γδ T cells. The interplay between TCR-mediated signaling and co-stimulatory interactions helps to fine-tune γδ T cell responses in different settings.
• Integration with other immune pathways: Crosstalk between γδ T cells and a variety of immune cells, including dendritic cells, natural killer cells, and other T cell subsets, contributes to the orchestration of immune responses.

Activation of γδ T Cells

Since their discovery in the early 1980s, γδ T cells have been found to play an important role in the development of tumors, infections, and autoimmune diseases. In early studies, scientists discovered that tumors and pathogens produce a class of lipid metabolites called "phosphor-antigens," which activate the largest class of γδ T cells in the human peripheral blood, the Vγ9Vδ2 T cells.

However, scientists were puzzled as to how these γδ T cells were able to sense these phospho-antigens hidden inside the target cells.

• A study reported that phosphor-antigens initiate γδ T cell activation through binding to the extracellular segment of BTN3A1 in target cells. However, there is controversy.
• Later a team published that the intracellular segment of BTN3A1 is the site of phosphor-antigen binding.

Immune Partners to Activate γδ T Cells

The γδ T-cell receptor (γδ TCR) is very sensitive to tumors and pathogens, and the binding strength of phosphor-antigens to BTN3A1 is not strong enough to activate γδ T-cells efficiently. Therefore, the researchers hypothesized that there is an "immune partner" of BTN3A1 in this process. After a long period of research, the team finally identified another "partner" - BTN2A1.

• BTN3A1 and BTN2A1 are jointly involved in the capture of phosphor-antigens. This finding perfectly explains the "superb" immunosurveillance ability of γδ T cells, i.e., even in the presence of a small amount of phospho-antigen, it can be efficiently "targeted" by the synergistic action of the two proteins.
• The binding of BTN3A1 and BTN2A1 inside the target cells induces the exposure of extracellular BTN3A1 and BTN2A1 epitopes, which effectively bind to the γδ TCR and finally realizes the activation of γδ T cells.

Recognition of phosphor-antigens by γδ T cells leads to new ideas for vaccination and treatment of autoimmune diseases. In addition, current TCR-T cell therapies around αβ T cells are fraught with challenges, and this study reveals a rapid pathway for γδ T cell-based TCR-T cell therapies, whereby a drug molecule can be substituted for the phosphor-antigen to function as a molecular glue, allowing γδ TCRs to efficiently recognize and attack tumor cells and infected cells.

Creative Biolabs is committed to utilizing new research advances to advance the development of TCR-γδ T-cell therapies.

Reference

1. Yuan, Linjie, et al. "Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells." Nature (2023): 1-9.