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Author Notes:

Cheng Zhu: cheng.zhu@bme.gatech.edu, Tel: 1-404-894-3269, Fax: 1-404-385-8109.

We thank S. Sambhara for providing F5 T cells; N. R. Gascoigne for providing CD8+/TCR- OT1 hybridoma; J. Altman for providing the H-2Kbα3A2 construct; H. He for experimental advice, V. Zarnitsyna for helping with the PP2 inhibition; J. Lou for structural analysis; J. Plowden and F. Zhang for technical assistance; and the NIH Tetramer Core Facility at Emory University for providing MHC monomers.

Authors have no conflicts of interest to declare.


Research Funding:

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.).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • TCR
  • LCK

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

Journal Title:



Volume 34, Number 1


, Pages 13-23

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© 2011 Elsevier Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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