Suppression of a Natural Killer Cell Response by Simian Immunodeficiency Virus Peptides.
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.
Department of Microbiology and Immunobiology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America.
Jamie L
JL
Schafer
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
Moritz
M
Ries
Department of Microbiology and Immunobiology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America.
Natasha
N
Guha
Division of Immunology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America.
Michelle
M
Connole
Division of Immunology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America.
Arnaud D
AD
Colantonio
Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Emmanuel J
EJ
Wiertz
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
Nancy A
NA
Wilson
Division of Immunology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America.
Amitinder
A
Kaur
Department of Microbiology and Immunobiology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America.
David T
DT
Evans
D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D057131:Immune Evasion; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008024:Ligands; D008253:Macaca mulatta; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054340:Receptors, KIR / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000502:physiology*; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D008024:Ligands; C110764:Mamu-A 01 antigen; D010455:Peptides; D054340:Receptors, KIR; D011994:Recombinant Proteins; D014764:Viral Proteins