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

PLoS Pathogens

Andrew Cogswell¹  Zachary B. Davis¹  Julie Boucau¹  Amanda Mertsching²  Kerry S. Campbell³  Hamish Scott⁴  Edward Barker⁵  Sylvie Le Gall⁶  Daniel Wambua⁶  Vicente Planelles⁶ 

[1] Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America;Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia;Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America;Division of Infection and Immunity and Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia;Fox Chase Cancer Center, Institute for Cancer Research, Philadelphia, Pennsylvania, United States of America;Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America

关键词: NK cells;    T cells;    Cell degranulation;    HIV-1;    HIV;    Cell staining;    Cloning;    Viral packaging;   

DOI  :  10.1371/journal.ppat.1005421

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY