Cytokines enhance human Vγ9Vδ2 T-cell TCR-dependent and TCR-independent effector functions.

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.

Targeting butyrophilins for cancer immunotherapy.

Vγ9Vδ2+ T cells form part of the innate immune repertoire and are activated by phosphorylated antigens produced by many bacteria and tumors. They have long been suggested as promising targets for anti-tumor therapies, but clinical trials so far have not shown major successes. Several recent discoveries could help to overcome these shortfalls, such as those leading to an improved understanding of the role of butyrophilin molecules BTN2A1 and BTN3A1, in Vγ9Vδ2+ T cell activation. Moreover, we propose that studies suggesting the presence of live bacteria in a variety of tumors (tumor microbiome), indicate that the latter might be harnessed as a source of high affinity bacterial phosphoantigen to trigger or enhance anti-tumor immune responses.

Immune recognition of phosphoantigen-butyrophilin molecular complexes by γδ T cells.

Gamma-delta (γδ) T cells are an important component of the immune system. They are often enriched in non-lymphoid tissues and exhibit diverse functional attributes including rapid activation, cytokine production, proliferation, and acquisition of cytotoxicity following both TCR-dependent and TCR-independent stimulation, but poor capacity for immunological memory. They can detect a broad range of antigens, although typically not peptide-MHC complexes in contrast to alpha-beta (αß) T cells. In humans, a prominent population of γδ T cells, defined as Vγ9Vδ2+ cells, reacts to small phosphorylated non-peptide "phosphoantigens" (pAgs). The molecular mechanism underpinning this recognition is poorly defined, but is known to involve butyrophilin family members and appears to involve indirect pAg recognition via alterations to butyrophilin molecular complexes. In this review, we discuss recent advances in our understanding of pAg recognition by γδ T cells including the role of butyrophilins and in particular, a newly described role for butyrophilin 2A1.

Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells.

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.