Empty conformers of HLA-B preferentially bind CD8 and regulate CD8+ T cell function

  1. Jie Geng
  2. John D Altman
  3. Sujatha Krishnakumar
  4. Malini Raghavan  Is a corresponding author
  1. University of Michigan, United States
  2. Yerkes National Primate Research Center, Emory University School of Medicine, United States
  3. Sirona Genomics, Immucor, Inc, United States

Abstract

When complexed with antigenic peptides, human leukocyte antigen (HLA) class I (HLA-I) molecules initiate CD8+ T cell responses via interaction with the T cell receptor (TCR) and co-receptor CD8. Peptides are generally critical for the stable cell surface expression of HLA-I molecules. However, for HLA-I alleles such as HLA-B*35:01, peptide-deficient (empty) heterodimers are thermostable and detectable on the cell surface. Additionally, peptide-deficient HLA-B*35:01 tetramers preferentially bind CD8 and to a majority of blood-derived CD8+ T cells via a CD8-dependent binding mode. Further functional studies reveal that peptide-deficient conformers of HLA-B*35:01 do not directly activate CD8+ T cells, but accumulate at the immunological synapse in antigen-induced responses, and enhance cognate peptide-induced cell adhesion and CD8+ T cell activation. Together, these findings indicate that HLA-I peptide occupancy influences CD8 binding affinity, and reveal a new set of regulators of CD8+ T cell activation, mediated by the binding of empty HLA-I to CD8.

Data availability

The data that support the findings of this study are openly available in Dryad at https://doi.org/10.5061/dryad.543pp71.

The following data sets were generated

Article and author information

Author details

  1. Jie Geng

    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  2. John D Altman

    Department of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, United States
    Competing interests
    No competing interests declared.
  3. Sujatha Krishnakumar

    Research and Development, Sirona Genomics, Immucor, Inc, Mountain View, United States
    Competing interests
    Sujatha Krishnakumar, is affiliated with the Sirona Genomics, where the HLA genotyping for our study was done. The author has no financial interests to declare.
  4. Malini Raghavan

    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States
    For correspondence
    malinir@umich.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1345-9318

Funding

NIH Office of the Director (AI044115)

  • Malini Raghavan

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

Ethics

Human subjects: Blood was collected from consented healthy donors for HLA genotyping and functional studies in accordance with a University of Michigan IRB approved protocol (HUM00071750).

Reviewing Editor

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

Publication history

  1. Received: March 2, 2018
  2. Accepted: April 23, 2018
  3. Accepted Manuscript published: May 9, 2018 (version 1)
  4. Version of Record published: June 6, 2018 (version 2)

Copyright

© 2018, Geng 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.

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  1. Jie Geng
  2. John D Altman
  3. Sujatha Krishnakumar
  4. Malini Raghavan
(2018)
Empty conformers of HLA-B preferentially bind CD8 and regulate CD8+ T cell function
eLife 7:e36341.
https://doi.org/10.7554/eLife.36341
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