A Conserved HIV-1-Derived Peptide Presented by HLA-E Renders Infected T-cells Highly Susceptible to Attack by NKG2A/CD94-Bearing Natural Killer Cells

Zachary B. Davis, Andrew Cogswell, Hamish Scott, Amanda Mertsching, Julie Boucau, Daniel Wambua, Sylvie Le Gall, Vicente Planelles, Kerry S. Campbell, Edward Barker

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Major histocompatibility class I (MHC-I)-specific inhibitory receptors on natural killer (NK) cells (iNKRs) tolerize mature NK cell responses toward normal cells. NK cells generate cytolytic responses to virus-infected or malignant target cells with altered or decreased MHC-I surface expression due to the loss of tolerizing ligands. The NKG2A/CD94 iNKR suppresses NK cell responses through recognition of the non-classical MHC-I, HLA-E. We used HIV-infected primary T-cells as targets in an in vitro cytolytic assay with autologous NK cells from healthy donors. In these experiments, primary NKG2A/CD94+ NK cells surprisingly generated the most efficient responses toward HIV-infected T-cells, despite high HLA-E expression on the infected targets. Since certain MHC-I-presented peptides can alter recognition by iNKRs, we hypothesized that HIV-1-derived peptides presented by HLA-E on infected cells may block engagement with NKG2A/CD94, thereby engendering susceptibility to NKG2A/CD94+ NK cells. We demonstrate that HLA-E is capable of presenting a highly conserved peptide from HIV-1 capsid (AISPRTLNA) that is not recognized by NKG2A/CD94. We further confirmed that HLA-C expressed on HIV-infected cells restricts attack by KIR2DL+ CD56dim NK cells, in contrast to the efficient responses by CD56bright NK cells, which express predominantly NKG2A/CD94 and lack KIR2DLs. These findings are important since the use of NK cells was recently proposed to treat latently HIV-1-infected patients in combination with latency reversing agents. Our results provide a mechanistic basis to guide these future clinical studies, suggesting that ex vivo-expanded NKG2A/CD94+ KIR2DL- NK cells may be uniquely beneficial.

Original languageEnglish (US)
Article numbere1005421
JournalPLoS pathogens
Volume12
Issue number2
DOIs
StatePublished - Feb 2016

Bibliographical note

Funding Information:
The study was funded by the following grants from the National Institutes of Health (initial of the authors with the following grants funded are in parentheses): R01 AI065361, R21 AI081681, R21 AI078749 (EB), R01 CA083859 (KSC), and U19 AI096113 (EB and VP), R01 AI112493 (SLG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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