Butyrophilin subfamily 3 member A (BTN3A) (BTN3A)

Butyrophilin subfamily 3 member A (BTN3A), also known as CD277, is a group of type I transmembrane proteins belonging to the immunoglobulin superfamily and structurally related to the B7 family of immune regulators [2, 7]. It consists of three isoforms—BTN3A1, BTN3A2, and BTN3A3—which share high homology in their extracellular domains [7, 11]. BTN3A1 is essential for the activation of Vγ9Vδ2 T cells, a subset of gamma-delta T cells that play a key role in immunosurveillance by sensing intracellular phosphoantigens [3, 14]. BTN3A2 and BTN3A3 support this process by regulating the stability and surface expression of BTN3A1 [14, 19]. In many cancers, BTN3A is overexpressed, making it an attractive target for immunotherapy [3, 16]. Drugs like the monoclonal antibody ICT01 target the extracellular domains of these proteins to bypass physiological activation and directly stimulate gamma-delta T cells to attack tumor cells [3, 4]. This mechanism is being explored for the treatment of various solid tumors and hematological malignancies, such as acute myeloid leukemia [4, 9]. Additionally, BTN3A can act as an immune checkpoint by interacting with CD45 to inhibit alpha-beta T cell responses [6, 18].

Other names

CD277BTN3Butyrophilin 3ABTN3A1BTN3A2BTN3A3Butyrophilin subfamily 3 member A1Butyrophilin subfamily 3 member A2Butyrophilin subfamily 3 member A3

Agonistic binding to the extracellular domain of BTN3A isoforms to induce a conformational change that activates Vγ9Vδ2 T cells, leading to the secretion of pro-inflammatory cytokines (e.g., IFN-gamma, TNF-alpha) and direct cytotoxic killing of tumor cells [3, 4, 6].