Two-step binding mechanism for T-cell receptor recognition of peptide MHC.
T cells probe a diverse milieu of peptides presented by molecules of the major histocompatibility complex (MHC) by using the T-cell receptor (TCR) to scan these ligands with high sensitivity and specificity. Here we describe a physical basis for this scanning process by studying the residues involved in both the initial association and the stable binding of TCR to peptide-MHC, using the well-characterized TCR and peptide-MHC pair of 2B4 and MCC-IE(k) (moth cytochrome c, residues 88 103). We show that MHC contacts dictate the initial association, guiding TCR docking in a way that is mainly independent of the peptide. Subsequently, MCC-IE(k) peptide contacts dominate stabilization, imparting specificity and influencing T-cell activation by modulating the duration of binding. This functional subdivision of the peptide-MHC ligand suggests that a two-step process for TCR recognition facilitates the efficient scanning of diverse peptide-MHC complexes on the surface of cells and also makes TCRs inherently crossreactive towards different peptides bound by the same MHC.
Wu
Lawren C
LC
Howard Hughes Medical Institute and Department of Microbiology and Immunology, Stanford University School of Medicine, B221 Beckman Center, Stanford, California 94305, USA.
Tuot
Delphine S
DS
Lyons
Daniel S
DS
Garcia
K Christopher
KC
Davis
Mark M
MM
D000818:Animals; D001665:Binding Sites; D015374:Biosensing Techniques; D003574:Cytochrome c Group / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006649:Histocompatibility Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007700:Kinetics; D018448:Models, Immunological; D008958:Models, Molecular; D009036:Moths; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D013379:Substrate Specificity; D013816:Thermodynamics
D003574:Cytochrome c Group; D018984:Epitopes, T-Lymphocyte; D006649:Histocompatibility Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell