Domestic Research Team Completes Key Piece of γδ T Cell Recognition Mechanism, Paving the Way for Breakthrough in γδ TCR-Based Immunotherapy

T cells are a core component of the immune system and are divided into two major subgroups: αβ and γδ. Among them, αβ T cells activate immune responses by recognizing peptide antigens presented by MHC molecules, a mechanism that has become a cornerstone of modern immunology. γδ T cells, discovered in 1984, are considered a "bridge" connecting innate immunity with adaptive immunity due to their rapid response capabilities against tumors and pathogens. Taking the most abundant γδ T cell subgroup in humans—Vγ9Vδ2 T cells—as an example, they achieve rapid recognition of abnormal cells by sensing "phosphoantigen" signals transmitted via the BTN3A1 protein on the target cell surface, which conveys intracellular metabolic products.

The early "extracellular binding hypothesis" proposed that phosphoantigens bind to the extracellular region of BTN3A1, but this theory could not explain the fact that phosphoantigens originate from inside target cells. In 2019, Zhang Yonghui's team at Tsinghua University demonstrated in *Immunity* through high-resolution crystal structures that phosphoantigens actually bind to the intracellular B30.2 domain of BTN3A1, thereby triggering an "inside-out" signaling mechanism. However, there is a notable contrast between the high sensitivity of γδ T-cell receptors (γδ TCR) in physiological environments and the limited binding strength between phosphoantigens and BTN3A1.

To explain this phenomenon, Zhang Yonghui speculated that there might be an "immune partner" for BTN3A1. After extensive research, the team eventually identified the key co-protein—BTN2A1. However, scientists in Australia at this time were the first to report in *Science* the direct binding of the extracellular domain of BTN2A1 to γδ TCR. This study failed to fully reveal why γδ T cells are able to monitor tumors and pathogens so efficiently.

In 2023, Zhang Yonghui and Guo Ruiting's teams reported in Nature that phosphoantigens act like "molecular glue," stably connecting BTN3A1 and BTN2A1 inside target cells, inducing conformational changes in their extracellular domains and exposing critical epitopes, thereby jointly activating γδ TCR. The study also found that other BTN family members, such as BTN3A2, are involved in this process.

The latest study published in *Immunity* fully reveals the recognition mechanism of this type of γδ T cell: Inside the target cell, BTN3A1 collaborates with BTN2A1 to bind phosphoantigens, enabling efficient sensing of intracellular metabolic changes; on the surface of the target cell, BTN3A2 forms a heterodimer with BTN3A1 and, together with BTN2A1, constructs a "molecular clamp" structure—one side clamping the Vγ9 chain of the TCR and the other side binding the apex region of the Vδ2 chain, driving conformational changes in the TCR to achieve highly efficient activation. This "clamp-like gripping" mechanism unifies the dual immune properties of γδ T cells at the structural level for the first time: rapid innate immune responses mediated by germline-encoded regions and specific adaptive immune recognition mediated by complementarity-determining regions (CDR3). Notably, the research team has also developed high-activity functional antibodies against BTN proteins, which not only help further elucidate the TCR recognition mechanism but also provide an important tool for subsequent clinical development.