Human Vγ9Vδ2 T cells mode of target recognition in a butyrophilin dependent manner

Room 306, Samgatha Block, Nila campus

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Human Vγ9Vδ2 T cells are a prominent subset of γδ T cells in peripheral blood and have gained significant attention in cancer immunotherapy due to their potent ability to eliminate cancer cells. Their TCRs are composed of a characteristic Vγ9JP rearranged γ-chain paired with a Vδ2- δ chain. Under conditions of cellular stress, pathogen infection, or tumorigenesis, target cells exhibit elevated levels of phosphorylated isoprenoid metabolites, collectively termed phosphoantigens (PAgs). Vγ9Vδ2 T cells recognise these elevated PAgs in a butyrophilin (BTN)-dependent manner, leading to target cell elimination. Therapeutic strategies, such as pharmacological derivatives of aminobisphosphonates (e.g., zoledronate), can enhance this antitumor activity by increasing PAg accumulation in tumours. Despite the therapeutic promise, the molecular mechanisms underlying Vγ9Vδ2 T cell activation remained poorly understood for years. However, recent breakthroughs, including the identification of BTN2 and BTN3 proteins, have illuminated critical aspects of antigen-dependent Vγ9Vδ2 T cell activation. Notably, the genes involved in BTN-mediated antigen recognition have co-evolved with certain mammalian lineages and are absent in rodents, limiting the applicability of small animal models for research. My ongoing work focuses on unravelling the  BTN-dependent modulation of T cells and other molecular modalities involved in Vγ9Vδ2 T cell response.