Pluto Bioinformatics

GSE106760: TCR transmembrane domain coordinates antigen triggering by regulating bilayer immersion and CD3 associations

Bulk RNA sequencing

Initial molecular details of cellular activation following T-cell receptor (TCR) ligation by pMHC remain unexplored. We determined the NMR structure of the TCR subunit transmembrane (TM) segment revealing a bipartite helix whose segmentation fostersdynamic movement. Positively charged TM residues Arg251 and Lys256 project from opposite faces of the helix, with Lys256 controlling immersion depth. Their modification causes step-wise reduction in associations with T-cell surface CD3 and CD3/CD3, respectively, leading to an activated transcriptome. Optical tweezers reveal that Arg251 and Lys256 mutations alter TCR-pMHC bond lifetimes, while mutations within interacting TCR connecting peptide and CD3 CxxC motif juxtamembrane elements selectively attenuate signal transduction. Our findings suggest that mechanical forces applied during pMHC ligation initiate T-cell activation by altering the disposition of those basic sidechains to rearrange TCR complex membrane topology and weaken TCR and CD3 associations. This TCR dissociative mechanism impacts future immunotherapy and synthetic receptor design on CAR-T cells. SOURCE: Kevin Bi (kevin_bi@dfci.harvard.edu) - Haining Lab Dana-Farber Cancer Institute