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

• Published in: Immunological reviews Vol. 251; no. 1; pp. 49 - 64
• Main Authors: Zhu, Cheng, Jiang, Ning, Huang, Jun, Zarnitsyna, Veronika I., Evavold, Brian D.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.01.2013
• Subjects: Animals; Antibodies; Antigen-presenting cells; CD3 antigen; cell activation; Cell Communication; Differentiation; Histocompatibility Antigens - immunology; Histocompatibility Antigens - metabolism; Humans; Immunity, Cellular; interaction network; Kinetics; Lipid bilayers; Lipid Bilayers - immunology; Lymphocytes T; Major histocompatibility complex; Major Histocompatibility Complex - immunology; Mechanotransduction, Cellular - immunology; Peptide Fragments - immunology; Peptide Fragments - metabolism; Protein Binding; Receptor Cross-Talk; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Signal Transduction - immunology; Surface Plasmon Resonance; T cells; T-cell receptor; T-cell receptors; Thermodynamics; two-dimensional affinity and kinetics
• ISSN: 0105-2896; 1600-065X; 1600-065X
• DOI: 10.1111/imr.12016

Summary 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.