Editors' ChoiceImmunology

T cell receptors communicate by movement

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Science Translational Medicine  12 Dec 2018:
Vol. 10, Issue 471, eaaw0522
DOI: 10.1126/scitranslmed.aaw0522

Abstract

Dynamic structural changes in the α chain transmembrane region convey T cell receptor signals.

Gene-engineered T cell therapies that employ T cell receptors (TCRs) or TCR components for the targeting of tumors or infections are being widely implemented in clinical trials. TCR signaling is fundamental to both natural TCRs and to novel chimeric antigen receptors (CARs), which recognize their targets through antibody-like domains and transmit activation signals through TCR signaling domains. Despite the long-recognized importance of TCRs in adaptive immunity and the central role of TCR signaling in new T cell–based therapies, the mechanisms guiding TCR signaling are incompletely understood. A recent paper by Brazin et al. sheds light on the dynamic structure and function of TCRs and how bioforces transfer TCR signals through the cell membrane.

The TCR complex is composed of paired αβ chains that determine antigen specificity by binding peptide presented by major histocompatibility complex (MHC) on another cell, and of paired ξξ chains, εγ chains, and εδ chains that activate intracellular signaling. Brazin et al. interrogated the TCR α chain transmembrane (TM) domain with nuclear magnetic resonance and electron paramagnetic resonance spectroscopy. They found that the TM domain is composed of a bipartite helix linked by a hinge region, and that it exists in a dynamic bistable state with an L-shaped conformation (L-state) that is favored in the absence of TCR ligation and a straightened conformation (E-state) that is induced by TCR ligation. Mutational studies with confocal microscopy and immunoprecipitation revealed that two TM amino acid residues govern noncovalent interactions with and spatial separation from TCR-complex ξ chain homodimers and ε chain heterodimers. Modification of these residues altered TCR signal–induced transcriptional programs and antigen recognition sensitivity, confirming their functional importance. The authors proposed a model in which TCR ligation causes α chain TM domain conformational changes and subunit localization to release the cytoplasmic tails of TCR subunits from the inner leaflet of the plasma membrane for phosphorylation of activation motif domains.

These findings have translational importance as they indicate that TCR signaling can be tuned by modification of the TCR α chain TM region to alter natural biomechanics. This knowledge creates a foundation for rational strategies to increase the sensitivity and potency of TCR-based signaling in therapeutic gene-engineered T cells, and it reveals another contrast in the mechanisms of TCR and CAR signaling.

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