TCR Nanoclusters as the Framework for Transmission of Conformational Changes and Cooperativity

Raquel Blanco,Balbino Alarcón

doi:10.3389/fimmu.2012.00115

Abstract

Increasing evidence favors the notion that, before triggering, the T cell antigen receptor (TCR) forms nanometer-scale oligomers that are called nanoclusters. The organization of the TCR in pre-existing oligomers cannot be ignored when analyzing the properties of ligand (pMHC) recognition and signal transduction. As with other membrane receptors, the existence of TCR oligomers points out to cooperativity phenomena. We review the data in support of conformational changes in the TCR as the basic principle to transduce the activation signal to the cytoplasm and the incipient data suggesting cooperativity within nanoclusters.

Highlights

The molecular mechanisms underlying the initiation of T cell antigen receptor (TCR) signaling are not completely understood
The archetypical example is this of G-protein-coupled receptors (GPCRs) which was originally proposed to oscillate between an inactive and an active state stabilized by ligand binding
Many receptors with intrinsic tyrosine kinase activity undergo ligand-induced conformational changes (Jiang and Hunter, 1999), as well as several receptors of immunological interest, including: integrins, the erythropoietin receptor, the tumor necrosis factor receptors, Fas, the interleukin 6 receptor, IFN receptors (Banner et al, 1993; Walter et al, 1995; Remy et al, 1999; Chan et al, 2000; Siegel et al, 2000; Krause et al, 2002; Murali et al, 2005; Strunk et al, 2008), and most important, Abbreviations: EM, electron microscopy; Forster’s resonance energy transfer (FRET), Forester’s resonance energy transfer; GPCRs, G-protein-coupled receptors; ITAM, immunoreceptor tyrosine-based activation motif; NMR, nuclear magnetic resonance; pMHC, major histocompatibility complex loaded with antigen peptide; PRS, proline-rich sequence; TCR, T cell antigen receptor

Summary

INTRODUCTION

The molecular mechanisms underlying the initiation of TCR signaling are not completely understood. The studies on the mechanisms of signal initiation by the TCR are perverted by models which try to explain some of the properties of antigen recognition by T cells, such as the discrimination between MHC loaded with self-peptides and MHC loaded with antigen peptides and the exquisite sensitivity of T cells to low doses of antigen, but that do not provide mechanistic insights into how signal is transmitted from the outside to the cytoplasm We have evidence that both crosslinking of the TCR and conformational changes are required for T cell activation (Minguet et al, 2007)

Conformational change and cooperativity phosphatases internalization

Inactive conformation