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Identification of a Porcine Liver Eomes^highT-bet^low NK Cell Subset That Resembles Human Liver Resident NK Cells.

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 (Eomes^highT-bet^low in man and vice versa in mouse). In pig, compared to blood NK cells which are CD3^-CD8?^high cells, the porcine liver contains an abundant additional CD3^-CD8?^dim NK cell subpopulation. In the current study, we show that this porcine CD3^-CD8?^dim 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 Eomes^highT-bet^low expression pattern. In addition, like its human counterpart, the porcine liver NK population is CD49e^- and CXCR6⁺. Furthermore, the porcine Eomes^highT-bet^low liver NK cell population is able to produce IFN-? 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 Eomes^highT-bet^low 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.

SUBMITTER: De Pelsmaeker S

PROVIDER: S-EPMC6836759 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Identification of a Porcine Liver Eomes<sup>high</sup>T-bet<sup>low</sup> NK Cell Subset That Resembles Human Liver Resident NK Cells.

De Pelsmaeker Steffi S Denaeghel Sofie S Hermans Leen L Favoreel Herman W HW

Frontiers in immunology 20191031

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 reside ...[more]

PMID: 31736976

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Project description:CD49a+ tissue resident NK cells have been implicated in memory-like NK cell responses, but while this population is well-characterized in mice and in humans, they are poorly described in non-human primates (NHP) which are particularly critical for modeling human viral infections. Others and we have shown that memory-like NK cells are enriched in the liver and because of the importance of NHP in modeling HIV infection, understanding the immunobiology of CD49a+ NK cells in SIV-infected rhesus macaques is critical to explore the role of this cell type in retroviral infections. In this study mononuclear cells isolated from livers, spleens, and peripheral whole blood were analyzed in acutely and chronically lentivirus-infected and experimentally-naïve Indian rhesus macaques (RM). NK cells were then identified as CD45+CD14-CD20-CD3-NKG2A/C+ cells and characterized using multiparametric flow-cytometry. Our data show that in RM, CD49a+ NK cells increase in the liver following retroviral infections [median = 5.2% (naïve) vs. median = 9.48% (SIV+) or median = 16.8% (SHIV+)]. In contrast, there is little change in CD49a+ NK frequencies in whole blood or spleens of matched animals. In agreement with human and murine data we also observed that CD49a+ NK cells were predominantly Eomeslow T-betlow, though these frequencies are elevated in infected animal cohorts. Functionally, our data suggests that infection alters TNF-α, IFN-γ, and CD107a expression in stimulated CD49a+ NK cells. Specifically, our analyses found a decrease in CD49a+ CD107a+ TNFα+ IFNγ- NK cells, with a simultaneous increase in CD49a+ CD107a+ TNFα- IFNγ+ NK cells and the non-responsive CD49a+ CD107a- TNFα- IFNγ- NK cell population following infection, suggesting both pathogenic and inflammatory changes in the NK cell functional profile. Our data also identified significant global differences in polyfunctionality between CD49a+ NK cells in the naïve and chronic (SHIV+) cohorts. Our work provides the first characterization of CD49a+ NK cells in tissues from RM. The significant similarities between CD49a+ NK cells from RM and what is reported from human samples justifies the importance of studying CD49a+ NK cells in this species to support preclinical animal model research.

Project description:Natural killer (NK) cells are innate lymphoid cells involved in the defense against virus-infected cells and tumor cells. NK cell phenotype and function is affected with age and cytomegalovirus (CMV) latent infection. Aging affects the frequency and phenotype of NK cells, and CMV infection also contributes to these alterations. Thus, a reduction of CD56bright NK cell subpopulation associated with age and an expansion of memory-like NK cells CD56dimCD57+NKG2C+ probably related to CMV seropositivity have been described. NK cells express T-bet and Eomes transcription factors that are necessary for the development of NK cells. Here, we analyze the effect of age and CMV seropositivity on the expression of CD300a and CD161 inhibitory receptors, and T-bet and Eomes transcription factors in NK cell subsets defined by the expression of CD56 and CD57. CD300a is expressed by the majority of NK cells. CD56bright NK cells express higher levels of CD300a than CD56dim NK cells. An increase in the expression of CD300a was associated with age, whereas a decreased expression of CD161 in CD56dim NK cells was associated with CMV seropositivity. In CD56dim NK cells, an increased percentage of CD57+CD300a+ and a reduction in the percentage of CD161+CD300a+ cells were found to be associated with CMV seropositivity. Regarding T-bet and Eomes transcription factors, CMV seropositivity was associated with a decrease of T-bethi in CD56dimCD57+ NK cells from young individuals, whereas Eomes expression was increased with CMV seropositivity in both CD56bright and CD56dimCD57+/- (from middle age and young individuals, respectively) and was decreased with aging in all NK subsets from the three group of age. In conclusion, CMV infection and age induce significant changes in the expression of CD300a and CD161 in NK cell subsets defined by the expression of CD56 and CD57. T-bet and Eomes are differentially expressed on NK cell subsets, and their expression is affected by CMV latent infection and aging.

Dataset Information

Identification of a Porcine Liver Eomes^highT-bet^low NK Cell Subset That Resembles Human Liver Resident NK Cells.

Publications

Identification of a Porcine Liver Eomes<sup>high</sup>T-bet<sup>low</sup> NK Cell Subset That Resembles Human Liver Resident NK Cells.

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Dataset Information

Identification of a Porcine Liver EomeshighT-betlow NK Cell Subset That Resembles Human Liver Resident NK Cells.

Publications

Identification of a Porcine Liver Eomes<sup>high</sup>T-bet<sup>low</sup> NK Cell Subset That Resembles Human Liver Resident NK Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Identification of a Porcine Liver Eomes^highT-bet^low NK Cell Subset That Resembles Human Liver Resident NK Cells.