Antigen ligation triggers a conformational change within the constant domain of the alphabeta T cell receptor.
Ligation of the alphabeta 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 alphabeta TCR results in a specific conformational change confined to the A-B loop within the alpha chain of the constant domain (Calpha). The apparent affinity constant of this A-B loop movement mirrored that of alphabeta TCR-pMHC ligation and was observed in two alphabeta 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 Calpha 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.
Beddoe
Travis
T
Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
Chen
Zhenjun
Z
Clements
Craig S
CS
Ely
Lauren K
LK
Bushell
Simon R
SR
Vivian
Julian P
JP
Kjer-Nielsen
Lars
L
Pang
Siew Siew
SS
Dunstone
Michelle A
MA
Liu
Yu Chih
YC
Macdonald
Whitney A
WA
Perugini
Matthew A
MA
Wilce
Matthew C J
MC
Burrows
Scott R
SR
Purcell
Anthony W
AW
Tiganis
Tony
T
Bottomley
Stephen P
SP
McCluskey
James
J
Rossjohn
Jamie
J
D000818:Animals; D000941:Antigens / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D008285:Major Histocompatibility Complex / Q000276:immunology; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000941:Antigens; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta