1. Immunology and Inflammation
Download icon

Structural variability and concerted motions of the T cell receptor - CD3 complex

  1. Prithvi R Pandey
  2. Bartosz Różycki
  3. Reinhard Lipowsky
  4. Thomas R Weikl  Is a corresponding author
  1. Max Planck Institute of Colloids and Interfaces, Germany
  2. Polish Academy of Sciences, Poland
Research Article
  • Cited 0
  • Views 686
  • Annotations
Cite this article as: eLife 2021;10:e67195 doi: 10.7554/eLife.67195

Abstract

We investigate the structural and orientational variability of the membrane-embedded T cell receptor (TCR) - CD3 complex in extensive atomistic molecular dynamics simulations based on the recent cryo-EM structure determined by Dong et al. (2019). We find that the TCR extracellular (EC) domain is highly variable in its orientation by attaining tilt angles relative to the membrane normal that range from 15° to 55°. The tilt angle of the TCR EC domain is both coupled to a rotation of the domain and to characteristic changes throughout the TCR - CD3 complex, in particular in the EC interactions of the C_ FG loop of the TCR, as well as in the orientation of transmembrane helices. The concerted motions of the membrane-embedded TCR - CD3 complex revealed in our simulations provide atomistic insights on conformational changes of the complex in response to tilt-inducing forces on antigen-bound TCRs.

Data availability

All 6000 molecular dynamics structures of the membrane-embedded TCR-CD3 complex used in the analysis have been deposited in the Edmond Open Research Data Repository under https://dx.doi.org/10.17617/3.5m.

The following data sets were generated

Article and author information

Author details

  1. Prithvi R Pandey

    Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Bartosz Różycki

    Institute of Physics, Polish Academy of Sciences, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  3. Reinhard Lipowsky

    Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8417-8567
  4. Thomas R Weikl

    Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
    For correspondence
    thomas.weikl@mpikg.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0911-5328

Funding

The authors declare that there was no funding for this work.

Reviewing Editor

  1. Michael L Dustin, University of Oxford, United Kingdom

Publication history

  1. Preprint posted: February 3, 2021 (view preprint)
  2. Received: February 3, 2021
  3. Accepted: September 6, 2021
  4. Accepted Manuscript published: September 7, 2021 (version 1)
  5. Version of Record published: October 11, 2021 (version 2)

Copyright

© 2021, Pandey et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 686
    Page views
  • 118
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    2. Immunology and Inflammation
    Dasmanthie DeSilva et al.
    Research Article

    Activation of T cells requires a rapid surge in cellular protein synthesis. However, the role of translation initiation in the early induction of specific genes remains unclear. Here, we show human translation initiation factor eIF3 interacts with select immune system related mRNAs including those encoding the T cell receptor (TCR) subunits TCRA and TCRB. Binding of eIF3 to the TCRA and TCRB mRNA 3’-untranslated regions (3’-UTRs) depends on CD28 coreceptor signaling and regulates a burst in TCR translation required for robust T cell activation. Use of the TCRA or TCRB 3’-UTRs to control expression of an anti-CD19 chimeric antigen receptor (CAR) improves the ability of CAR-T cells to kill tumor cells in vitro. These results identify a new mechanism of eIF3-mediated translation control that can aid T cell engineering for immunotherapy applications.

    1. Immunology and Inflammation
    Shahanshah Khan et al.
    Research Article Updated

    The pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here, we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induced inflammatory cytokines and chemokines, including IL-6, IL-1β, TNFα, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and nucleocapsid (N) proteins. When stimulated with extracellular S protein, human and mouse lung epithelial cells also produced inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly were non-inflammatory, but elicited an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-κB pathway in a MyD88-dependent manner. Further, such an activation of the NF-κB pathway was abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein-induced IL-6, TNF-α, and IL-1β in wild-type, but not Tlr2-deficient mice. Notably, upon recognition of S protein, TLR2 dimerizes with TLR1 or TLR6 to activate the NF-κB pathway. Taken together, these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.