Two-Stage Cooperative T Cell Receptor-Peptide Major Histocompatibility Complex-CD8 Trimolecular Interactions Amplify Antigen Discrimination

• Type of Material: Article
• Authors: Ning Jiang, Georgia Institute of Technology; Jun Huang, Georgia Institute of Technology; Lindsay J. Edwards, Emory University; Baoyu Liu, Georgia Institute of Technology; Yan Zhang, Georgia Institute of Technology; Carrie D. Beal, Emory University; Brian Evavold, Emory University; Cheng Zhu, Emory University
• Language: English
• Date: 2011-01-28
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.immuni.2010.12.017
• Title of Journal or Parent Work: Immunity
• ISSN: 1074-7613
• Volume: 34
• Issue: 1
• Start Page: 13
• End Page: 23
• Grant/Funding Information: This work was supported by NIH grants AI38282 and AI060799 (to C.Z.) and AI056017; and National Multiple Sclerosis Society Grant RG4047-A-3 (to B.D.E.).
• Keywords: Immunology; CD8 CORECEPTOR; KINETICS; ACTIVATION; Science & Technology; RECOGNITION; TCR; MICROCLUSTERS; LIGAND-BINDING; LCK; RECRUITMENT; Life Sciences & Biomedicine; AFFINITY
• Research Categories: Health Sciences, Immunology; Engineering, Biomedical

Abstract

The T cell receptor (TCR) and CD8 bind peptide-major histocompatibility complex (pMHC) glycoproteins to initiate adaptive immune responses, yet the trimolecular binding kinetics at the T cell membrane is unknown. By using a micropipette adhesion frequency assay, we show that this kinetics has two stages. The first consists of TCR-dominant binding to agonist pMHC. This triggers a second stage consisting of a step increase in adhesion after a one second delay. The second-stage binding requires Src family kinase activity to initiate CD8 binding to the same pMHC engaged by the TCR. This induced trimeric-cooperative interaction enhances adhesion synergistically to favor potent ligands, which further amplifies discrimination. Our data reveal a TCR-CD8 positive-feedback loop involved in initial signaling steps that is sensitive to a single pMHC is rapid, reversible, synergistic, and peptide discriminative.