Abstract
Natural killer (NK) cells are cells of the innate immunity and play an important role in the defense against viral infections and cancer, but also contribute to shaping adaptive immune responses. Long-lived tissue-resident NK cells have been described in man and mouse, particularly in the liver, contributing to the idea that the functional palette of NK cells may be broader than originally thought, and may include memory-like responses and maintaining tissue homeostasis. Remarkably, liver resident (lr)NK cells in man and mouse show substantial species-specific differences, in particular reverse expression patterns of the T-box transcription factors Eomesodermin (Eomes) and T-bet (EomeshighT-betlow in man and vice versa in mouse). In pig, compared to blood NK cells which are CD3−CD8αhigh cells, the porcine liver contains an abundant additional CD3−CD8αdim NK cell subpopulation. In the current study, we show that this porcine CD3−CD8αdim liver NK population is highly similar to its human lrNK counterpart and therefore different from mouse lrNK cells. Like human lrNK cells, this porcine NK cell population shows an EomeshighT-betlow expression pattern. In addition, like its human counterpart, the porcine liver NK population is CD49e− and CXCR6+. Furthermore, the porcine EomeshighT-betlow liver NK cell population is able to produce IFN-γ upon IL-2/12/18 stimulation but lacks the ability to kill K562 or pseudorabies virus-infected target cells, although limited degranulation could be observed upon incubation with K562 cells or upon CD16 crosslinking. All together, these results show that porcine EomeshighT-betlow NK cells in the liver strongly resemble human lrNK cells, and therefore indicate that the pig may represent a unique model to study the function of these lrNK cells in health and disease.
Highlights
Natural killer (NK) cells are important members of the innate immune system and play a crucial role in the defense against viral infections and cancer, mainly because of their ability to kill virus-infected cells and malignant cells
To evaluate the possibility that the pig harbors lrNK cells, an isolation procedure of liver NK cells was performed based on previous studies that showed that mouse and human lrNK cells reside in the liver sinusoids and are enriched when the excised liver is flushed with saline [7, 8, 29, 30]
In line with the recent notion that in human, EomeshighT-betlow lrNK cells can already be detected early in development [31], we found that EomeshighTbetlow liver NK cells are present in mature, 6 month old pigs and in 5-week old piglets (Supplementary Figure 1)
Summary
Natural killer (NK) cells are important members of the innate immune system and play a crucial role in the defense against viral infections and cancer, mainly because of their ability to kill virus-infected cells and malignant cells. NK cells have traditionally been considered to be Porcine Liver Eomeshigh T-betlow NK Cells short-lived, increasing evidence in man and mouse indicates that long-lived NK cell subsets exist, in the liver [4] Such long-lived NK cell subpopulations contribute to the notion that the functional repertoire of NK cells may be broader than originally thought, e.g., including memory-like responses and maintenance of tissue homeostasis [4, 5]. CyTOF analysis revealed that lack of CD49e expression is a discriminating marker for human lrNK cells [7] Given these discrepancies between human and murine lrNK cells, additional/alternative animal model species may be useful to study these particular aspects of human NK cell biology. The pig represents an attractive model to study the function of these lrNK cells in health and disease
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