Butyrophilin 2A1–Butyrophilin 3A1 heteromeric complex (BTN2A1–BTN3A1 complex)

The BTN2A1–BTN3A1 heteromeric complex is a pivotal molecular assembly on the surface of various cells, including tumor and infected cells, that serves as the primary sensor for intracellular phosphoantigens (pAgs) like HMBPP and IPP (1.4.1, 1.5.1). This complex is essential for the activation of Vgamma9Vdelta2 T cells, a unique subset of gamma-delta T cells with potent anti-tumor and anti-pathogen activity (1.1.3, 1.3.4). Mechanistically, pAgs bind to the intracellular B30.2 domain of BTN3A1, acting as a 'molecular glue' that triggers an association with the intracellular domain of BTN2A1 (1.4.1, 1.5.1). This intracellular interaction induces a conformational change in the extracellular domains, allowing the complex to be recognized by the Vgamma9Vdelta2 T cell receptor (TCR) (1.3.1, 1.4.3). In oncology, the complex is targeted by therapeutic antibodies such as ICT01, which bypass the need for pAg accumulation to directly activate T cell-mediated cytotoxicity against a broad range of hematologic and solid tumors (1.1.2, 1.2.1). Beyond its role in gamma-delta T cell activation, the complex also modulates alpha-beta T cell responses by regulating the segregation of CD45 from the immune synapse (1.2.1, 1.5.2).

Other names

BTN2A1–BTN3A1 heteromerHMBPP receptor complexCD277–BTN2A1 complexButyrophilin subfamily 2 member A1 and Butyrophilin subfamily 3 member A1 complex

Agonistic monoclonal antibodies bind to the extracellular domains of BTN3A, inducing conformational changes or multimerization that promote the formation of the BTN2A1–BTN3A1 complex, thereby mimicking phosphoantigen-induced activation of Vgamma9Vdelta2 T cells.