Gamma delta (γδ) T cells are essential to protective immunity. In humans, most γδ T cells express Vγ9Vδ2+ T cell receptors (TCRs) that respond to phosphoantigens (pAgs) produced by cellular pathogens and overexpressed by cancers. However, the molecular targets recognized by these γδTCRs are unknown. Here, we identify butyrophilin 2A1 (BTN2A1) as a key ligand that binds to the Vγ9+ TCR γ chain. BTN2A1 associates with another butyrophilin, BTN3A1, and these act together to initiate responses to pAg. Furthermore, binding of a second ligand, possibly BTN3A1, to a separate TCR domain incorporating Vδ2 is also required. This distinctive mode of Ag-dependent T cell activation advances our understanding of diseases involving pAg recognition and creates opportunities for the development of γδ T cell–based immunotherapies.

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The three main classes of lymphocytes bearing rearranged antigen receptors are B cells, αβ T cells, and γδ T cells. In humans, γδ T cells represent about 1 to 10% of circulating PBMCs 1,2 and are named as such because their antigen receptors are a product of recombination-activating gene (RAG)-mediated somatic gene rearrangement of variable (V), diversity (D), and joining (J) gene segments that are derived from the gamma and delta T cell receptor (TCR) gene loci. Akin to αβTCR gene rearrangement during αβ T cell development, the resulting rearranged gamma and delta chains heterodimerize

Humans have a minor lymphocyte population of gamma-delta (γδ) T cells. The majority of these express a recombined Vγ9Vδ2 T cell receptor (TCR) attractive to immunotherapy. This distinct TCR conveys reactivity to phosphorylated antigens (pAg) that derive from pathogens or accumulate inside tumour cells. Such T cell responses are regulated by butyrophilin (BTN) 3A1 and other membrane-related proteins present on antigen-presenting cells. However, the activation mechanism and direct molecular ligand recognised by the γδ TCR remain a crucial unresolved question. Herein, we used pAg-reactive TCR probes in a whole-genome screen to identify BTN2A1 as an essential ligand. In further investigation, we elucidated its functionality working in cis with BTN3A1. Also, a mutational analysis unveiled critical regions of the γδ TCR are positioned at opposite sides. We locate germ-line encoded residues of the Vγ9 chain were responsible for BTN2A1 binding, whereas two amino-acids of the Vδ2 chain were necessary for a complete response to pAg. In conclusion, we propose a dual-ligand complex model that senses pAg to evoke immune responses, wherein BTN2A1 sets the framework to develop new opportunities on γδ T cell-based immunotherapies.

Read more about EJI's first-time authors Vγ9Vδ2 T cells can recognize various molecules associated with cellular stress or transformation, providing a unique avenue for the treatment of cancers or infectious diseases. Nonetheless, Vγ9Vδ2 T-cell-based immunotherapies frequently achieve suboptimal efficacies in vivo. Enhancing the cytotoxic effector function of Vγ9Vδ2 T cells is one potential avenue through which the immunotherapeutic potential of this subset may be improved. We compared the use of four pro-inflammatory cytokines on the effector phenotype and functions of in vitro expanded Vγ9Vδ2 T cells, and demonstrated TCR-independent cytotoxicity mediated through CD26, CD16, and NKG2D, which could be further enhanced by IL-23, IL-18, and IL-15 stimulation throughout expansion. This work defines promising culture conditions that could improve Vγ9Vδ2 T-cell-based immunotherapies and furthers our understanding of how this subset might recognize and target transformed or infected cells.

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