Suppression of a Natural Killer Cell Response by Simian Immunodeficiency Virus Peptides

PLoS Pathogens

Emmanuel J. Wiertz¹  David T. Evans²  Jamie L. Schafer²  Natasha Guha²  Moritz Ries³  Nancy A. Wilson³  Michelle Connole⁴  Amitinder Kaur⁴  Arnaud D. Colantonio⁴ 

[1] Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands;Department of Microbiology and Immunobiology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America;Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, United States of America;Division of Immunology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America

关键词: NK cells;    SIV;    Major histocompatibility complex;    Cell binding;    Cell staining;    Viral replication;    Macaque;    HIV-1;   

DOI  :  10.1371/journal.ppat.1005145

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Natural killer (NK) cell responses in primates are regulated in part through interactions between two highly polymorphic molecules, the killer-cell immunoglobulin-like receptors (KIRs) on NK cells and their major histocompatibility complex (MHC) class I ligands on target cells. We previously reported that the binding of a common MHC class I molecule in the rhesus macaque, Mamu-A1*002, to the inhibitory receptor Mamu-KIR3DL05 is stabilized by certain simian immunodeficiency virus (SIV) peptides, but not by others. Here we investigated the functional implications of these interactions by testing SIV peptides bound by Mamu-A1*002 for the ability to modulate Mamu-KIR3DL05+ NK cell responses. Twenty-eight of 75 SIV peptides bound by Mamu-A1*002 suppressed the cytolytic activity of primary Mamu-KIR3DL05+ NK cells, including three immunodominant CD8+ T cell epitopes previously shown to stabilize Mamu-A1*002 tetramer binding to Mamu-KIR3DL05. Substitutions at C-terminal positions changed inhibitory peptides into disinhibitory peptides, and vice versa, without altering binding to Mamu-A1*002. The functional effects of these peptide variants on NK cell responses also corresponded to their effects on Mamu-A1*002 tetramer binding to Mamu-KIR3DL05. In assays with mixtures of inhibitory and disinhibitory peptides, low concentrations of inhibitory peptides dominated to suppress NK cell responses. Consistent with the inhibition of Mamu-KIR3DL05+ NK cells by viral epitopes presented by Mamu-A1*002, SIV replication was significantly higher in Mamu-A1*002+ CD4+ lymphocytes co-cultured with Mamu-KIR3DL05+ NK cells than with Mamu-KIR3DL05- NK cells. These results demonstrate that viral peptides can differentially affect NK cell responses by modulating MHC class I interactions with inhibitory KIRs, and provide a mechanism by which immunodeficiency viruses may evade NK cell responses.

【 授权许可】

CC BY