Heterozygosity for the common perforin mutation, p.A91V, impairs the cytotoxicity of primary natural killer cells from healthy individuals

Immunology and Cell Biology
Imran G HouseIlia Voskoboinik

Abstract

The production and delivery of functional perforin (PRF; PRF1 gene) by cytotoxic lymphocytes maintains immune homeostasis and tumour immune surveillance. In humans, inheritance of the common PRF1 polymorphism, p.A91V, (c.272C>T) found in 8-9% of the Caucasian population, with another mutated allele resulting in reduced PRF function or trafficking, has been shown to result in hyperinflammatory diseases and/or haematological cancers. In this study, we sought to investigate the function of p.A91V on a wild-type (WT) perforin background. We first developed an assay that distinguishes the relative levels of transcription of individual PRF1 alleles, including p.A91V. The p.A91V allele was seen to be expressed at similar levels as the WT allele in primary human natural killer (NK) cells, ruling out that allelic expression imbalance influenced their function. We then demonstrated that the p.A91V mutation results in protein misfolding and an appreciable reduction in NK-cell cytotoxicity in healthy carriers of p.A91V. We propose that this level of cytotoxic dysfunction may readily account for the predisposition to immune-mediated disease in individuals homozygous for p.A91V. Also, the fact that monoallelic mutations of PRF1 decrease NK-c...Continue Reading

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Citations

Oct 16, 2015·Hematology/oncology Clinics of North America·Sarah Nikiforow
Nov 26, 2015·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Matthias Voss, Yenan T Bryceson
Sep 14, 2016·Oncoimmunology·Mohammed S ChaudhryIlia Voskoboinik
Jul 7, 2017·Leukemia & Lymphoma·Bruna Maria Bereta SouzaHelio Moraes-Souza
Feb 9, 2018·International Immunology·Grant S Schulert, Scott W Canna
Aug 11, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Conor J KearneyJane Oliaro
May 23, 2015·Nature Reviews. Immunology·Ilia VoskoboinikJoseph A Trapani
Feb 14, 2019·Cancer·Alexandra LöfstedtMarie Meeths
Sep 1, 2016·Journal of Neuroinflammation·Robin C WillenbringAaron J Johnson
Sep 29, 2020·Journal of Clinical Immunology·Fahad AlsohimeYousef Mohammed Hawsawi
Apr 16, 2020·Genes and Immunity·Grant S Schulert, Randy Q Cron
May 20, 2018·Science Immunology·Conor J KearneyJane Oliaro
Jul 27, 2020·Haematologica·Oscar Cabrera-MaranteEstela Paz-Artal
Jan 18, 2019·Cancer Immunology Research·Jessica MichieJane Oliaro
Jan 19, 2021·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·Krista KuitwaardRuth Huizinga
Dec 2, 2020·Haematologica·Oscar Cabrera-MaranteEstela Paz-Artal
Aug 8, 2021·Nature Communications·Emma V PetleyPhillip K Darcy

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