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

Abstract
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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.

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

(2018) Data from: Empty conformers of HLA-B preferentially bind CD8 and regulate CD8+ T cell function
Available at Dryad Digital Repository under a CC0 Public Domain Dedication.

https://doi.org/10.5061/dryad.543pp71

Article and author information

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).

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.