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

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Cite this article as: eLife 2018;7:e36341 doi: 10.7554/eLife.36341

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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.

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Author details

Jie Geng

Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States

Competing interests
No competing interests declared.
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.
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.
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.

"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

Michael L Dustin, University of Oxford, United Kingdom

Publication history

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

Copyright

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.