5 years ago

Phosphoantigen-induced conformational change of butyrophilin 3A1 (BTN3A1) and its implication on V{gamma}9V{delta}2 T cell activation [Immunology and Inflammation]

Phosphoantigen-induced conformational change of butyrophilin 3A1 (BTN3A1) and its implication on V{gamma}9V{delta}2 T cell activation [Immunology and Inflammation]
Benoit Roux, Christopher T. Boughter, Joseph R. Sachleben, Georgios Skiniotis, Marta T. Borowska, Jeffrey T. Tarrasch, Erin J. Adams, Siyi Gu, Wioletta I. Nawrocka

Human Vγ9Vδ2 T cells respond to microbial infections as well as certain types of tumors. The key initiators of Vγ9Vδ2 activation are small, pyrophosphate-containing molecules called phosphoantigens (pAgs) that are present in infected cells or accumulate intracellularly in certain tumor cells. Recent studies demonstrate that initiation of the Vγ9Vδ2 T cell response begins with sensing of pAg via the intracellular domain of the butyrophilin 3A1 (BTN3A1) molecule. However, it is unknown how downstream events can ultimately lead to T cell activation. Here, using NMR spectrometry and molecular dynamics (MD) simulations, we characterize a global conformational change in the B30.2 intracellular domain of BTN3A1 induced by pAg binding. We also reveal by crystallography two distinct dimer interfaces in the BTN3A1 full-length intracellular domain, which are stable in MD simulations. These interfaces lie in close proximity to the pAg-binding pocket and contain clusters of residues that experience major changes of chemical environment upon pAg binding. This suggests that pAg binding disrupts a preexisting conformation of the BTN3A1 intracellular domain. Using a combination of biochemical, structural, and cellular approaches we demonstrate that the extracellular domains of BTN3A1 adopt a V-shaped conformation at rest, and that locking them in this resting conformation without perturbing their membrane reorganization properties diminishes pAg-induced T cell activation. Based on these results, we propose a model in which a conformational change in BTN3A1 is a key event of pAg sensing that ultimately leads to T cell activation.

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