Insights from in situ analysis of TCR-pMHC recognition: response of an interaction network

• Type of Material: Article
• Authors: Cheng Zhu, Emory University; Ning Jiang, University of Texas Austin; Jun Huang, Stanford University; Veronika I. Zarnitsyna, Emory University; Brian Evavold, Emory University
• Language: English
• Date: 2013-01-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.
• Final Published Version (URL): http://dx.doi.org/10.1111/imr.12016
• Title of Journal or Parent Work: Immunological Reviews
• ISSN: 0105-2896
• Volume: 251
• Issue: 1
• Start Page: 49
• End Page: 64
• Grant/Funding Information: This work was supported by NIH grants R01GM096187 (CZ and VIZ), K99AG040149 (NJ), the Cancer Prevention and Research Institute of Texas grant R1120 (NJ), NIH grants R01NS062358 and R01NS071518 (BDE) and the National Multiple Sclerosis Society grant RG4482 (BDE).
• Keywords: MHC; SELECTIN GLYCOPROTEIN LIGAND-1; MAJOR HISTOCOMPATIBILITY COMPLEX; two-dimensional affinity and kinetics; ACTIVATION; cell activation; Science & Technology; Immunology; T-cell receptors; IMMUNOLOGICAL SYNAPSE; 2-DIMENSIONAL DISSOCIATION-CONSTANT; CONTACT-AREA FRAP; interaction network; AFFINITY; T cells; BINDING-KINETICS; Life Sciences & Biomedicine; T-CELL-RECEPTOR
• Research Categories: Health Sciences, Immunology

Abstract

Recognition of peptide presented by the major histocompatibility complex (pMHC) molecule by the T-cell receptor (TCR) determines T-cell selection, development, differentiation, fate, and function. Despite intensive studies on the structures, thermodynamic properties, kinetic rates, and affinities of TCR-pMHC interactions in the past two decades, questions regarding the functional outcome of these interactions, i.e. how binding of the αβ TCR heterodimer with distinct pMHCs triggers different intracellular signals via the adjacent CD3 components to produce different T-cell responses, remain unclear. Most kinetic measurements have used surface plasmon resonance, a three-dimensional (3D) technique in which fluid-phase receptors and ligands are removed from their cellular environment. Recently, several two-dimensional (2D) techniques have been developed to analyze molecular interactions on live T cells with pMHCs presented by surrogate antigen-presenting cells or supported planar lipid bilayers. The insights from these in situ analyses have provided a sharp contrast of the 2D network biology approach to the 3D reductionist approach and prompted rethinking of our current views of T-cell triggering. Based on these insights, we propose a mechanochemical coupled triggering hypothesis to explain why the in situ kinetic parameters differ so much from their 3D counterparts, yet correlate so much better with T-cell functional responses.