Premium
Heterozygosity for the common perforin mutation, p.A91V, impairs the cytotoxicity of primary natural killer cells from healthy individuals
Author(s) -
House Imran G,
Thia Kevin,
Brennan Amelia J,
Tothill Richard,
Dobrovic Alexander,
Yeh Wei Z,
Saffery Richard,
Chatterton Zac,
Trapani Joseph A,
Voskoboinik Ilia
Publication year - 2015
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/icb.2015.1
Subject(s) - perforin , cytotoxic t cell , biology , immune system , allele , cytotoxicity , immunology , natural killer cell , loss of heterozygosity , mutation , genetics , cancer research , gene , cd8 , in vitro
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‐cell cytotoxicity should be considered in individuals presenting with the manifestations of immune deficiency states that impinge on NK‐cell cytotoxicity.