TAPBPR mediates peptide dissociation from MHC class I using a leucine lever

  1. Florin Tudor Ilca
  2. Andreas Neerincx
  3. Clemens Hermann
  4. Ana Marcu
  5. Stefan Stefvanovic
  6. Janet E Deane
  7. Louise H Boyle  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. University of Cape Town, South Africa
  3. University of Tübingen, Germany

Abstract

Tapasin and TAPBPR are known to perform peptide editing on major histocompatibility complex class I (MHC I) molecules, however, the precise molecular mechanism(s) involved in this process remain largely enigmatic. Here, using immunopeptidomics in combination with novel cell-based assays that assess TAPBPR-mediate peptide exchange, we reveal a critical role for the K22-D35 loop of TAPBPR in mediating peptide exchange on MHC I. We identify a specific leucine within this loop that enables TAPBPR to facilitate peptide dissociation from MHC I. Moreover, we delineate the molecular features of the MHC I F pocket required for TAPBPR to promote peptide dissociation in a loop-dependent manner. These data reveal that chaperone-mediated peptide editing of MHC I can occur by different mechanisms dependent on the C-terminal residue that the MHC I accommodates in its F pocket and provide novel insights that may inform the therapeutic potential of TAPBPR manipulation to increase tumour immunogenicity.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files regarding the lists of peptides presented on MHC class I have been provided for Figures 5

The following data sets were generated

Article and author information

Author details

  1. Florin Tudor Ilca

    Department of Pathology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    Florin Tudor Ilca, Some aspects of the work included in this manuscript form part of a recent patent application. Applicant: Cambridge Enterprise Limited. Application number: 1801323.5, Status: Pending.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6582-8007
  2. Andreas Neerincx

    Department of Pathology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    Andreas Neerincx, Some aspects of the work included in this manuscript form part of a recent patent application. Applicant: Cambridge Enterprise Limited. Application number: 1801323.5, Status: Pending.
  3. Clemens Hermann

    Department of Integrative Biomedical Sciences, Division of Chemical and Systems Biology, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
    Competing interests
    No competing interests declared.
  4. Ana Marcu

    Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0808-8097
  5. Stefan Stefvanovic

    Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
  6. Janet E Deane

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4863-0330
  7. Louise H Boyle

    Department of Pathology, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    lhb22@cam.ac.uk
    Competing interests
    Louise H Boyle, Some aspects of the work included in this manuscript form part of a recent patent application. Applicant: Cambridge Enterprise Limited. Application number: 1801323.5, Status: Pending.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3105-6555

Funding

Wellcome (104647/Z/14/Z)

  • Andreas Neerincx
  • Louise H Boyle

South African Medical Research Council

  • Clemens Hermann

Royal Society (UF100371)

  • Janet E Deane

Bosch-Forschungsstiftung

  • Ana Marcu
  • Stefan Stefvanovic

Wellcome (109076/Z/15/A)

  • Florin Tudor Ilca

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kai Wucherpfennig

Version history

  1. Received: July 15, 2018
  2. Accepted: November 28, 2018
  3. Accepted Manuscript published: November 28, 2018 (version 1)
  4. Version of Record published: December 27, 2018 (version 2)

Copyright

© 2018, Ilca 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

  • 2,146
    Page views
  • 312
    Downloads
  • 35
    Citations

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

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)

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

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

  1. Florin Tudor Ilca
  2. Andreas Neerincx
  3. Clemens Hermann
  4. Ana Marcu
  5. Stefan Stefvanovic
  6. Janet E Deane
  7. Louise H Boyle
(2018)
TAPBPR mediates peptide dissociation from MHC class I using a leucine lever
eLife 7:e40126.
https://doi.org/10.7554/eLife.40126

Further reading

    1. Immunology and Inflammation
    Atomu Yamaguchi, Noriaki Maeshige ... Hidemi Fujino
    Research Article

    The regulation of inflammatory responses is an important intervention in biological function and macrophages play an essential role during inflammation. Skeletal muscle is the largest organ in the human body and releases various factors which mediate anti-inflammatory/immune modulatory effects. Recently, the roles of extracellular vesicles (EVs) from a large variety of cells are reported. In particular, EVs released from skeletal muscle are attracting attention due to their therapeutic effects on dysfunctional organs and tissues. Also, ultrasound (US) promotes release of EVs from skeletal muscle. In this study, we investigated the output parameters and mechanisms of US-induced EV release enhancement and the potential of US-treated skeletal muscle-derived EVs in the regulation of inflammatory responses in macrophages. High-intensity US (3.0 W/cm2) irradiation increased EV secretion from C2C12 murine muscle cells via elevating intracellular Ca2+ level without negative effects. Moreover, US-induced EVs suppressed expression levels of pro-inflammatory factors in macrophages. miRNA sequencing analysis revealed that miR-206-3p and miR-378a-3p were especially abundant in skeletal myotube-derived EVs. In this study we demonstrated that high-intensity US promotes the release of anti-inflammatory EVs from skeletal myotubes and exert anti-inflammatory effects on macrophages.

    1. Genetics and Genomics
    2. Immunology and Inflammation
    Huiyun Lyu, Guohua Yuan ... Yan Shi
    Research Article

    Thymus-originated tTregs and in vitro induced iTregs are subsets of regulatory T cells. While they share the capacity of immune suppression, their stabilities are different, with iTregs losing their phenotype upon stimulation or under inflammatory milieu. Epigenetic differences, particularly methylation state of Foxp3 CNS2 region, provide an explanation for this shift. Whether additional regulations, including cellular signaling, could directly lead phenotypical instability requires further analysis. Here, we show that upon TCR (T cell receptor) triggering, SOCE (store-operated calcium entry) and NFAT (nuclear factor of activated T cells) nuclear translocation are blunted in tTregs, yet fully operational in iTregs, similar to Tconvs. On the other hand, tTregs show minimal changes in their chromatin accessibility upon activation, in contrast to iTregs that demonstrate an activated chromatin state with highly accessible T cell activation and inflammation related genes. Assisted by several cofactors, NFAT driven by strong SOCE signaling in iTregs preferentially binds to primed-opened T helper (TH) genes, resulting in their activation normally observed only in Tconv activation, ultimately leads to instability. Conversely, suppression of SOCE in iTregs can partially rescue their phenotype. Thus, our study adds two new layers, cellular signaling and chromatin accessibility, of understanding in Treg stability, and may provide a path for better clinical applications of Treg cell therapy.