Natural killer (NK) cells have long been considered to be a homogenous population of innate lymphocytes with limited phenotypic and functional diversity. However, recent findings have revealed that ...these cells comprise a large number of distinct populations with diverse characteristics. Some of these characteristics may relate to their developmental origin, and others represent differences in differentiation that are influenced by factors such as tissue localization and imprints by viral infections. In this Review, we provide a comprehensive overview of the emerging knowledge about the development, differentiation and function of human NK cell populations, with a particular focus on NK cells in peripheral tissues.
Natural killer (NK) cells play an important role in innate immune responses to viral infections. Here, we review recent insights into the role of NK cells in viral infections, with particular ...emphasis on human studies. We first discuss NK cells in the context of acute viral infections, with flavivirus and influenza virus infections as examples. Questions related to activation of NK cells, homing to infected tissues and the role of tissue-resident NK cells in acute viral infections are also addressed. Next, we discuss NK cells in the context of chronic viral infections with hepatitis C virus and HIV-1. Also covered is the role of adaptive-like NK cell expansions as well as the appearance of CD56
NK cells in the course of chronic infection. Specific emphasis is then placed in viral infections in patients with primary immunodeficiencies affecting NK cells. Not least, studies in this area have revealed an important role for NK cells in controlling several herpesvirus infections. Finally, we address new data with respect to the activation of NK cells and NK cell function in humans infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) giving rise to coronavirus disease 2019 (COVID-19).
Immune exhaustion is a hallmark of chronic viral infections. However, pathogen eradication can result in reinvigorated immune responses. Indeed, this was recently suggested for antigen‐specific CD8+ ...T cells and NK cells in HCV‐infected patients receiving an interferon‐free treatment regimen. Mucosal‐associated invariant T (MAIT) cells are evolutionarily conserved innate‐like effector T cells. Here, we show that MAIT cells are severely diminished in frequency in chronic HCV‐infection, and in this regard the most affected immune cell type in peripheral blood of humans with this disease. Residual MAIT cells show an activated phenotype with high expression of granzyme B, HLA‐DR, PD‐1, and CD69 as well as altered transcription factor expression and suppressed responsiveness to MR1‐dependent antigen stimulation. In contrast to other immune cells, MAIT cells are not reinvigorated after successful HCV‐clearance using interferon‐free therapy. The present results hence demonstrate persistent immune cell‐dysfunction in humans despite successful elimination of a chronic pathogen.
Loss of peripheral blood MAIT cells represents a major immunological phenotype in patients with chronic HCV‐infection. Residual MAIT cells were highly activated and exhibited suppressed responsiveness after E. coli stimulation. The observed phenotype was not reinvigorated after successful HCV‐clearance using interferon‐free therapy.
Although NK cells are considered innate, recent studies in mice revealed the existence of a unique lineage of hepatic CD49a(+)DX5(-) NK cells with adaptive-like features. Development of this NK cell ...lineage is, in contrast to conventional NK cells, dependent on T-bet but not Eomes. In this study, we describe the identification of a T-bet(+)Eomes(-)CD49a(+) NK cell subset readily detectable in the human liver, but not in afferent or efferent hepatic venous or peripheral blood. Human intrahepatic CD49a(+) NK cells express killer cell Ig-like receptor and NKG2C, indicative of having undergone clonal-like expansion, are CD56(bright), and express low levels of CD16, CD57, and perforin. After stimulation, CD49a(+) NK cells express high levels of inflammatory cytokines but degranulate poorly. CD49a(+) NK cells retain their phenotype after expansion in long-term in vitro cultures. These results demonstrate the presence of a likely human counterpart of mouse intrahepatic NK cells with adaptive-like features.
Although natural killer (NK) cells are well known for their ability to kill tumors, few studies have addressed the interactions between resting (nonactivated) NK cells and freshly isolated human ...tumors. Here, we show that human leukocyte antigen class I(low) tumor cells isolated directly from patients with advanced ovarian carcinoma trigger degranulation by resting allogeneic NK cells. This was paralleled by induction of granzyme B and caspase-6 activities in the tumor cells and significant tumor cell lysis. Ovarian carcinoma cells displayed ubiquitous expression of the DNAX accessory molecule-1 (DNAM-1) ligand PVR and sparse/heterogeneous expression of the NKG2D ligands MICA/MICB and ULBP1, ULBP2, and ULBP3. In line with the NK receptor ligand expression profiles, antibody-mediated blockade of activating receptor pathways revealed a dominant role for DNAM-1 and a complementary contribution of NKG2D signaling in tumor cell recognition. These results show that resting NK cells are capable of directly recognizing freshly isolated human tumor cells and identify ovarian carcinoma as a potential target for adoptive NK cell-based immunotherapy.
Natural killer (NK) cells are affected by infection with human cytomegalovirus (HCMV) manifested by increased expression of the HLA‐E binding activating receptor NKG2C. We here show that HCMV ...seropositivity was associated with a profound expansion of NKG2C+CD56dim NK cells in patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Multi‐color flow cytometry revealed that the expanded NKG2C+CD56dim NK cells displayed a highly differentiated phenotype, expressed high amounts of granzyme B and exhibited polyfunctional responses (CD107a, IFN‐γ, and TNF‐α) to stimulation with antibody‐coated as well as HLA‐E expressing target cells but not when stimulated with IL‐12/IL‐18. More importantly, NKG2C+CD56dim NK cells had a clonal expression pattern of inhibitory killer cell immunoglobulin‐like receptors (KIRs) specific for self‐HLA class I molecules, with predominant usage of KIR2DL2/3. KIR engagement dampened NKG2C‐mediated activation suggesting that such biased expression of self‐specific KIRs may preserve self‐tolerance and limit immune‐pathology during viral infection. Together, these findings shed new light on how the human NK‐cell compartment adjusts to HCMV infection resulting in clonal expansion and differentiation of educated and polyfunctional NK cells.
The biliary tract is a complex tubular organ system spanning from the liver to the duodenum. It is the site of numerous acute and chronic disorders, many of unknown origin, that are often associated ...with cancer development and for which there are limited treatment options. Cholangiocytes with proinflammatory capacities line the lumen and specialised types of immune cells reside in close proximity. Recent technological breakthroughs now permit spatiotemporal assessments of immune cells within distinct niches and have increased our understanding of immune cell tissue residency. In this review, a comprehensive overview of emerging knowledge on the immunobiology of the biliary tract system is provided, with a particular emphasis on the role of distinct immune cells in biliary disorders.
Infection is a serious complication in patients with cirrhosis. Mucosal-associated invariant T (MAIT) cells are involved in the immune defense against infections and known to be impaired in several ...chronic conditions, including cirrhosis. Here, we evaluated if MAIT cell levels in peripheral blood are associated with risk of bacterial infections in patients with cirrhosis.
Patients with cirrhosis seen at the Karolinska University Hospital, Stockholm, Sweden, between 2016 and 2019 were included. Levels of MAIT cells in peripheral blood were determined using flow cytometry. Baseline and follow-up data after at least two years of follow-up were collected by chart review for the primary outcome (bacterial infection) and secondary outcomes (decompensation and death). Competing risk and Cox regression were performed.
We included 106 patients with cirrhosis. The median MAIT cells fraction in the circulation was 0.8% in cirrhosis compared to 6.1% in healthy controls. In contrast to our hypothesis, we found an association in the adjusted analysis between relatively preserved MAIT cell levels, and a slightly higher risk to develop bacterial infections (adjusted subdistribution hazard ratio (aSHR) 1.15 (95%CI = 1.01-1.31). However, MAIT cell levels were not associated with the risk of hepatic decompensation (aSHR 1.19 (95%CI = 0.91-1.56)) nor with death (adjusted hazard ratio 1.10 (95%CI = 0.97-1.22)).
Relatively preserved MAIT cell levels in blood of patients with cirrhosis were associated with a somewhat higher risk of bacterial infections. The clinical relevance of this might not be strong. MAIT cells might however be an interesting biomarker to explore in future studies.
Diversity is a central requirement for the immune system's capacity to adequately clear a variety of different infections. As such, natural killer (NK) cells represent a highly diverse population of ...innate lymphocytes important in the early response against viruses. Yet, the extent to which a chronic pathogen affects NK cell diversity is largely unknown. Here we study NK cell functional diversification in chronic hepatitis C virus (HCV) infection. High-dimensional flow cytometer assays combined with stochastic neighbor embedding analysis reveal that chronic HCV infection induces functional imprinting on human NK cells that is largely irreversible and persists long after successful interventional clearance of the virus. Furthermore, HCV infection increases inter-individual, but decreases intra-individual, NK cell diversity. Taken together, our results provide insights into how the history of infections affects human NK cell diversity.
Natural killer (NK) cells are lymphocytes of the innate immune system that, following differentiation from CD56bright to CD56dim cells, have been thought to retain fixed functional and phenotypic ...properties throughout their lifespan. In contrast to this notion, we here show that CD56dim NK cells continue to differentiate. During this process, they lose expression of NKG2A, sequentially acquire inhibitory killer cell inhibitory immunoglobulin-like receptors and CD57, change their expression patterns of homing molecules, and display a gradual decline in proliferative capacity. All cellular intermediates of this process are represented in varying proportions at steady state and appear, over time, during the reconstitution of the immune system, as demonstrated in humanized mice and in patients undergoing hematopoietic stem cell transplantation. CD56dim NK-cell differentiation, and the associated functional imprint, occurs independently of NK-cell education by interactions with self–human leukocyte antigen class I ligands and is an essential part of the formation of human NK-cell repertoires.
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