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
  • 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.