KIR3DS1 directs NK cell-mediated protection against human adenovirus infections

Johannes M Jung, Wilhelm Ching, Martin E Baumdick, Helga Hofmann-Sieber, Jens B Bosse, Tobias Koyro, Kimberly J Möller, Lucy Wegner, Annika Niehrs, Kristina Russu, Mareike Ohms, Wenli Zhang, Anja Ehrhardt, Kevin Duisters, Eric Spierings, Angelique Hölzemer, Christian Körner, Suze A Jansen, Sven Peine, Ingo KönigsMarc Lütgehetmann, Daniel Perez, Konrad Reinshagen, Caroline A Lindemans, Marcus Altfeld, Mirjam Belderbos, Thomas Dobner, Madeleine J Bunders

Research output: Contribution to journalArticlepeer-review

Abstract

Human adenoviruses (HAdVs) are a major cause for disease in children, in particular after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, effective therapies for HAdV infections in immunocompromised hosts are lacking. To decipher immune recognition of HAdV infection and determine new targets for immune-mediated control, we used an HAdV infection 3D organoid system, based on primary human intestinal epithelial cells. HLA-F, the functional ligand for the activating NK cell receptor KIR3DS1, was strongly up-regulated and enabled enhanced killing of HAdV5-infected cells in organoids by KIR3DS1+ NK cells. In contrast, HLA-A and HLA-B were significantly down-regulated in HAdV5-infected organoids in response to adenoviral E3/glycoprotein19K, consistent with evasion from CD8+ T cells. Immunogenetic analyses in a pediatric allo-HSCT cohort showed a reduced risk to develop severe HAdV disease and faster clearance of HAdV viremia in children receiving KIR3DS1+/HLA-Bw4+ donor cells compared with children receiving non–KIR3DS1+/HLA-Bw4+ cells. These findings identify the KIR3DS1/HLA-F axis as a new target for immunotherapeutic strategies against severe HAdV disease.

Original languageEnglish
Pages (from-to)eabe2942
JournalScience immunology
Volume6
Issue number63
DOIs
Publication statusPublished - 17 Sep 2021

Keywords

  • A549 Cells
  • Adenovirus Infections, Human/immunology
  • Adenoviruses, Human/immunology
  • HEK293 Cells
  • Humans
  • Killer Cells, Natural/immunology
  • Receptors, KIR3DS1/immunology

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