9dpe

Publication Abstract from PubMed

Target cells trigger Vgamma9Vdelta2 T cell activation by signaling the intracellular accumulation of phospho-antigen metabolites (pAgs) through Butyrophilin (BTN)-3A1 and BTN2A1 to the Vgamma9Vdelta2 T cell receptor (TCR). An incomplete understanding of the molecular dynamics in this signaling complex hampers Vgamma9Vdelta2 T cell immunotherapeutic efficacy. A panel of engineered alpha-BTN3A1 and alpha-BTN2A1 antibody (mAb) reagents was used to probe the roles of BTN3A1 and BTN2A1 in pAg signaling. Modified alpha-BTN3A1 mAbs with increased inter-Fab distances establish that tight clustering of BTN3A1 is not necessary to stimulate Vgamma9Vdelta2 T cell activation, and that antagonism may occur through occlusion of a critical binding interaction between BTN3A1 and a yet unknown co-receptor. Finally, a panel of additional alpha-BTN2A1 antagonists utilize different biophysical mechanisms to compete with Vgamma9Vdelta2 TCRs for BTN2A1 binding. The complex structures of BTN2A1 ectodomain and Fabs from three antagonist mAbs provide molecular insights into BTN2A1 epitopes critical for pAg-signaling.

Mapping the extracellular molecular architecture of the pAg-signaling complex with alpha-Butyrophilin antibodies.,Ramesh A, Roy S, Slezak T, Fuller J, Graves H, Mamedov MR, Marson A, Kossiakoff AA, Adams EJ Sci Rep. 2025 Apr 9;15(1):12162. doi: 10.1038/s41598-025-94347-w. PMID:40204806^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.