We collaborate with Dr. Wiemer from our department to study the mechanisms by which immune cells detect antigens. Recently, butyrophilin proteins have gained interest as distantly-related B7 proteins which function in activation of both traditional CD4+ and CD8+ T cells as well as non-traditional T cells expressing the gamma delta T cell receptor. We were among several groups to determine that phosphoantigens are ligands of the internal domain of a transmembrane butyrophilin 3 isoform (BTN3A1).
BTN3A1 contains an extracellular immunoglobulin-like (IgV/IgC) domain, a transmembrane helix (TM), and an intracellular B30.2 domain connected to the TM helix by a juxta-membrane (JM) region. While the ligand binding site is now clear, it remains unknown how ligand binding to BTN3A1 leads to T cell activation. Multiple models have been put forward, ranging from a heterotrimeric to a homodimeric models. We have found that phosphoantigen binding to the intracellular B30.2 domain not only causes structural changes in the JM region but, potentially, affects receptor oligomeric state. We believe that perturbations of the full intracellular domain, which contains the JM in addition to the B30.2, in target cells are driving critical conformational and clustering changes in the extracellular portion of the receptors that stimulate counter receptors on gamma delta T cells.