Antigen ligation triggers a conformational change within the constant domain of the αβ T cell receptor

Beddoe, Travis, Chen, Zhenjun, Clements, Craig S., Ely, Lauren K., Bushell, Simon R., Vivian, Julian P., Kjer-Nielsen, Lars, Pang, Siew Siew, Dunstone, Michelle A., Liu, Yu Chih, Macdonald, Whitney A., Perugini, Matthew A., Wilce, Matthew C.J., Burrows, Scott R., Purcell, Anthony W., Tiganis, Tony, Bottomley, Stephen P., McCluskey, James and Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 2009. Antigen ligation triggers a conformational change within the constant domain of the αβ T cell receptor. Immunity 30 (6) , pp. 777-788. 10.1016/j.immuni.2009.03.018

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Abstract

Ligation of the αβ T cell receptor (TCR) by a specific peptide-loaded major histocompatibility complex (pMHC) molecule initiates T cell signaling via the CD3 complex. However, the initial events that link antigen recognition to T cell signal transduction remain unclear. Here we show, via fluorescence-based experiments and structural analyses, that MHC-restricted antigen recognition by the αβ TCR results in a specific conformational change confined to the A-B loop within the α chain of the constant domain (Cα). The apparent affinity constant of this A-B loop movement mirrored that of αβ TCR-pMHC ligation and was observed in two αβ TCRs with distinct pMHC specificities. The Ag-induced A-B loop conformational change could be inhibited by fixing the juxtapositioning of the constant domains and was shown to be reversible upon pMHC disassociation. Notably, the loop movement within the Cα domain, although specific for an agonist pMHC ligand, was not observed with a pMHC antagonist. Moreover, mutagenesis of residues within the A-B loop impaired T cell signaling in an in vitro system of antigen-specific TCR stimulation. Collectively, our findings provide a basis for the earliest molecular events that underlie Ag-induced T cell triggering.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QR Microbiology > QR180 Immunology
Uncontrolled Keywords:	molimmuno
Publisher:	Elsevier
ISSN:	1074-7613
Last Modified:	24 Oct 2022 11:31
URI:	https://orca.cardiff.ac.uk/id/eprint/48466

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