2. Academic Validation
  3. Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1

Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1

  • Nat Immunol. 2016 Sep;17(9):1067-74. doi: 10.1038/ni.3513.
Wilfredo F Garcia-Beltran 1,  Angelique Hölzemer 1 2 3,  Gloria Martrus 2,  Amy W Chung 1,  Yovana Pacheco 1 4,  Camille R Simoneau 1,  Marijana Rucevic 1,  Pedro A Lamothe-Molina 1,  Thomas Pertel 5,  Tae-Eun Kim 1,  Haley Dugan 1,  Galit Alter 1,  Julie Dechanet-Merville 6,  Stephanie Jost 1,  Mary Carrington 1 7,  Marcus Altfeld 1 2
Affiliations

Affiliations

  • 1 Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA.
  • 2 Heinrich-Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
  • 3 First Department of Internal Medicine, University Medical Centre Eppendorf, Hamburg, Germany.
  • 4 Departamento de Matemáticas, Facultad de Ciencias, Universidad Nuestra Señora del Rosario, Bogotá, Colombia.
  • 5 Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 6 CNRS, UMR 5164, Université de Bordeaux, Bordeaux, France.
  • 7 Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
PMID: 27455421 DOI: 10.1038/ni.3513
Abstract

The activating natural killer (NK)-cell receptor KIR3DS1 has been linked to the outcome of various human diseases, including delayed progression of disease caused by human immunodeficiency virus type 1 (HIV-1), yet a ligand that would account for its biological effects has remained unknown. We screened 100 HLA class I proteins and found that KIR3DS1 bound to HLA-F, a result we confirmed biochemically and functionally. Primary human KIR3DS1(+) NK cells degranulated and produced Antiviral cytokines after encountering HLA-F and inhibited HIV-1 replication in vitro. Activation of CD4(+) T cells triggered the transcription and surface expression of HLA-F mRNA and HLA-F protein, respectively, and induced binding of KIR3DS1. HIV-1 Infection further increased the transcription of HLA-F mRNA but decreased the binding of KIR3DS1, indicative of a mechanism for evading recognition by KIR3DS1(+) NK cells. Thus, we have established HLA-F as a ligand of KIR3DS1 and have demonstrated cell-context-dependent expression of HLA-F that might explain the widespread influence of KIR3DS1 in human disease.

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