Explore the vast range of titles available.

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant of concern (VOC) has destabilized global efforts to control the impact of coronavirus disease 2019 (COVID-19). Recent data have suggested that B.1.1.529 can readily infect people with naturally acquired or vaccine-induced immunity, facilitated in some cases by viral escape from antibodies that neutralize ancestral SARS-CoV-2. However, severe disease appears to be relatively uncommon in such individuals, highlighting a potential role for other components of the adaptive immune system. We report here that SARS-CoV-2 spike-specific CD4 + and CD8 + T cells induced by prior infection or BNT162b2 vaccination provide extensive immune coverage against B.1.1.529. The median relative frequencies of SARS-CoV-2 spike-specific CD4 + T cells that cross-recognized B.1.1.529 in previously infected or BNT162b2-vaccinated individuals were 84% and 91%, respectively, and the corresponding median relative frequencies for SARS-CoV-2 spike-specific CD8 + T cells were 70% and 92%, respectively. Pairwise comparisons across groups further revealed that SARS-CoV-2 spike-reactive CD4 + and CD8 + T cells were functionally and phenotypically similar in response to the ancestral strain or B.1.1.529. Collectively, our data indicate that established SARS-CoV-2 spike-specific CD4 + and CD8 + T cell responses, especially after BNT162b2 vaccination, remain largely intact against B.1.1.529. Peripheral ancestral SARS-CoV-2 spike-specific CD4 + and CD8 + T cells induced by BNT162b2 vaccination cross-react to the Omicron variant at higher levels than those induced by prior SARS-CoV-2 infection.

Key Points Natural killer (NK) cells can be swiftly mobilized by danger signals and are among the earliest arrivals in target organs of disease. However, the role of NK cells in regulating inflammatory responses is far from completely understood in different organs. It is often complex and sometimes paradoxical. The phenotypes and functions of NK cells in the liver, mucosal tissues, uterus, pancreas, joints and brain are influenced by the unique cellular interactions and the local microenvironment within each organ. Hepatic NK cells exhibit an activated phenotype with high levels of cytotoxic effector molecules. These cells have been implicated in promoting liver injury and inhibiting liver fibrosis and regeneration. The liver is also enriched in NK cells with memory-like adaptive immune features. NK cells are detected in healthy lymphoid tissues of the lung, skin and gut, and are recruited to these tissues during infection or inflammation. In the gastrointestinal tract, classical NK cells and a variety of innate lymphoid cells, such as the family of lymphoid tissue-inducer (LTi) cells, are likely to have crucial roles in controlling inflammatory responses. NK cells represent the major lymphocyte subset in the pregnant uterus, with a unique phenotype resembling an early developmental state. Emerging evidence indicates that these cells play a crucial part in mediating the uterine vascular adaptations to pregnancy and promoting the maintenance of healthy pregnancy. In non-obese diabetic (NOD) mice, NK cells are recruited early to the pancreas, become locally activated and then adopt a hyporesponsive phenotype. Although NK cells have a pathogenic role in the natural progression of diabetes in NOD mice, they contribute to diabetes protection induced by complete Freund's adjuvant and to islet allograft tolerance induced by co-stimulatory blockade. NK cells in the inflamed joint uniquely express receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), which promote osteoclast differentiation. Although NK cells have a pathogenic role in collagen-induced arthritis in mice, they are also crucial for protection against antibody-induced arthritis mediated by CpG oligonucleotides. Studies in a mouse model of multiple sclerosis have shown that NK cells arrive in the central nervous system (CNS) before pathogenic T cells and have a protective role in the development of CNS inflammation, probably by killing CNS-resident microglia that prime effector T cells. During evolution, different organs might have evolved distinct ways to recruit and influence the effector functions of NK cells. Once we understand these mechanisms, the next challenge will be to exploit this information for harnessing NK cells to develop prophylactic and therapeutic measures against infectious agents, tumours and inflammatory diseases. Each tissue in our body contains a unique microenvironment that can differentially shape immune reactivity. In this Review article, Shi et al . describe how organ-specific factors influence natural killer cell homing and phenotype, and discuss the local molecular and cellular interactions that determine the protective or pathogenic functions of natural killer cells in the different tissues. Natural killer (NK) cells can be swiftly mobilized by danger signals and are among the earliest arrivals at target organs of disease. However, the role of NK cells in mounting inflammatory responses is often complex and sometimes paradoxical. Here, we examine the divergent phenotypic and functional features of NK cells, as deduced largely from experimental mouse models of pathophysiological responses in the liver, mucosal tissues, uterus, pancreas, joints and brain. Moreover, we discuss how organ-specific factors, the local microenvironment and unique cellular interactions may influence the organ-specific properties of NK cells.

Key Points Natural killer (NK) cells have the ability to lyse tumour cells without the requirement for prior immune sensitization of the host. NK-cell recognition of target cells is tightly regulated by processes involving the integration of signals delivered from multiple activating and inhibitory receptors. Insights into the molecular specificities that regulate NK-cell function have led to new possibilities to design NK-cell-based immunotherapeutic strategies against human cancer. Strategies of NK-cell immunotherapy include activation of endogenous NK cells, NK-cell-mediated graft-versus-tumour (GVT) effects in the context of haematopoietic allogeneic stem-cell transplantation (SCT), and adoptive transfer of allogeneic NK cells. Endogenous NK cells may be activated by cytokines, immunomodulatory drugs, and agonists of activating receptors or by blockade of inhibitory killer-cell immunoglobulin-like receptor (KIR) with monoclonal antibodies, thereby augmenting tumour-cell recognition by NK cells. NK cells may also be genetically engineered to shift the balance towards NK-cell activation. NK cells have been shown to mediate GVT effects in allogeneic haematopoietic SCT. Future criteria for donor selection may involve the selection of KIR–ligand-mismatched donors with a large alloreactive NK-cell subset. Conditioning regimens will probably be required for survival and in vivo expansion of adoptively transferred NK cells. Apart from preventing rejection, such regimens may eradicate regulatory T cells and promote access to homeostatic cytokines, including IL-15. Tumour-cell susceptibility to NK-cell lysis may be predicted by characterizing the expression of activating receptor ligands on tumour cells, as well as the expression of ligands for inhibitory receptors (MHC class I molecules). Such phenotypic analysis may be combined with direct testing of freshly isolated tumour cells for their susceptibility to NK-cell lysis ex vivo . Combinatorial therapies, in which NK cells represent one important mediator, may further potentiate the clinical efficacy of NK-cell immunotherapy. Natural killer cells were so named because of their ability to lyse tumour cells. Although initial studies have provided encouraging results, several challenges remain in optimizing the use of NK cells in therapeutic settings, as is described in this Review. Current insights into the molecular specificities that regulate natural killer (NK)-cell function suggest that it might be possible to design NK-cell-based immunotherapeutic strategies against human cancer. Here, we describe evidence for NK-cell targeting of human tumours and address crucial questions that, in our opinion, require consideration for the development of successful NK-cell-based therapies. Appropriately used, we predict that NK cells will have a role, both directly and in combination with other treatment modalities, in future treatment of cancer.

Human lung tissue-resident NK cells (trNK cells) are likely to play an important role in host responses towards viral infections, inflammatory conditions and cancer. However, detailed insights into these cells are still largely lacking. Here we show, using RNA sequencing and flow cytometry-based analyses, that subsets of human lung CD69 + CD16 − NK cells display hallmarks of tissue-residency, including high expression of CD49a, CD103, and ZNF683 , and reduced expression of SELL , S1PR5 , and KLF2/3 . CD49a + CD16 − NK cells are functionally competent, and produce IFN-γ, TNF, MIP-1β, and GM-CSF. After stimulation with IL-15, they upregulate perforin, granzyme B, and Ki67 to a similar degree as CD49a − CD16 − NK cells. Comparing datasets from trNK cells in human lung and bone marrow with tissue-resident memory CD8 + T cells identifies core genes co-regulated either by tissue-residency, cell-type or location. Together, our data indicate that human lung trNK cells have distinct features, likely regulating their function in barrier immunity. Detailed characterizations of human lung tissue-resident natural killer (trNK) cells, which potentially regulate local immune responses, is still lacking. Here the authors show that lung CD69 +  CD16 – NK cells express tissue-residency markers, produce effector cytokines, and are distinct, feature-wise, from lung CD8 + memory T cells or trNK in other tissues.

Since the outset of the COVID-19 pandemic, increasing evidence suggests that the innate immune responses play an important role in the disease development. A dysregulated inflammatory state has been proposed as a key driver of clinical complications in COVID-19, with a potential detrimental role of granulocytes. However, a comprehensive phenotypic description of circulating granulocytes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–infected patients is lacking. In this study, we used high-dimensional flow cytometry for granulocyte immunophenotyping in peripheral blood collected from COVID-19 patients during acute and convalescent phases. Severe COVID-19 was associated with increased levels of both mature and immature neutrophils, and decreased counts of eosinophils and basophils. Distinct immunotypes were evident in COVID-19 patients, with altered expression of several receptors involved in activation, adhesion, and migration of granulocytes (e.g., CD62L, CD11a/b, CD69, CD63, CXCR4). Paired sampling revealed recovery and phenotypic restoration of the granulocytic signature in the convalescent phase. The identified granulocyte immunotypes correlated with distinct sets of soluble inflammatory markers, supporting pathophysiologic relevance. Furthermore, clinical features, including multiorgan dysfunction and respiratory function, could be predicted using combined laboratory measurements and immunophenotyping. This study provides a comprehensive granulocyte characterization in COVID-19 and reveals specific immunotypes with potential predictive value for key clinical features associated with COVID-19.

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 important immune cells for mediating antiviral immunity. Here the authors show that chronic hepatitis C virus infection in human can imprint lasting functional phenotypes in NK cells to increase their inter-individual but decrease intra-individual diversity.

Hantaviruses, zoonotic RNA viruses belonging to the order Bunyavirales, cause two severe acute diseases in humans, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Hantavirus-infected patients show strong cytotoxic lymphocyte responses and hyperinflammation; however, infected cells remain mostly intact. Hantaviruses were recently shown to inhibit apoptosis in infected cells. By inhibiting granzyme B- and TRAIL-mediated apoptosis, hantaviruses specifically and efficiently inhibit cytotoxic lymphocyte-mediated killing of infected cells. Hantaviruses also strongly inhibit apoptosis triggered intrinsically; i.e., initiated through intracellular activation pathways different from those used by cytotoxic lymphocytes. However, insights into the latter mechanisms are currently largely unknown. Here, we dissected the mechanism behind how hantavirus infection, represented by the HFRS-causing Hantaan virus and the HPS-causing Andes virus, results in resistance to staurosporine-induced apoptosis. Less active caspase-8 and caspase-9, and consequently less active caspase-3, was observed in infected compared to uninfected staurosporine-exposed cells. While staurosporine-exposed uninfected cells showed massive release of pro-apoptotic cytochrome C into the cytosol, this was not observed in infected cells. Further, hantaviruses prevented activation of BAX and mitochondrial outer membrane permeabilization (MOMP). In parallel, a significant increase in levels of the pro-survival factor BCL-2 was observed in hantavirus-infected cells. Importantly, direct inhibition of BCL-2 by the inhibitor ABT-737, as well as silencing of BCL-2 by siRNA, resulted in apoptosis in staurosporine-exposed hantavirus-infected cells. Overall, we here provide a tentative mechanism by which hantaviruses protect infected cells from intrinsic apoptosis at the mitochondrial level by inducing an increased expression of the pro-survival factor BCL-2, thereby preventing MOMPs and subsequent activation of caspases. The variety of mechanisms used by hantaviruses to ensure survival of infected cells likely contribute to the persistent infection in natural hosts and may play a role in immunopathogenesis of HFRS and HPS in humans.

The gut and oral microbiome is altered in people living with HIV (PLWH). While antiretroviral treatment (ART) is pivotal in restoring immune function in PLWH, several studies have identified an association between specific antiretrovirals, particularly integrase inhibitors (INSTI), and weight gain. In our study, we explored the differences in the oral and gut microbiota of PLWH under different ART regimens, and its correlation to Body Mass Index (BMI). Fecal and salivary samples were collected from PLWH (n = 69) and healthy controls (HC, n = 80). We performed taxonomy analysis to determine the microbial composition and relationship between microbial abundance and ART regimens, BMI, CD4 + T-cell count, CD4/CD8 ratio, and ART duration. PLWH showed significantly lower richness compared to HC in both the oral and gut environment. The gut microbiome composition of INSTI-treated individuals was enriched with Faecalibacterium and Bifidobacterium , whereas non-nucleotide reverse transcriptase inhibitor (NNRTI)-treated individuals were enriched with Gordonibacter , Megasphaera, and Staphylococcus . In the oral microenvironment, Veillonella was significantly more abundant in INSTI-treated individuals and Fusobacterium and Alloprevotella in the NNRTI-treated individuals. Furthermore, Bifidobacterium and Dorea were enriched in gut milieu of PLWH with high BMI. Collectively, our findings identify distinct microbial profiles, which are associated with different ART regimens and BMI in PLWH on successful ART, thereby highlighting significant effects of specific antiretrovirals on the microbiome.

Orthohantaviruses, previously known as hantaviruses, are zoonotic viruses that can cause hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS) in humans. The HPS-causing Andes virus (ANDV) and the HFRS-causing Hantaan virus (HTNV) have anti-apoptotic effects. To investigate if this represents a general feature of orthohantaviruses, we analysed the capacity of six different orthohantaviruses – belonging to three distinct phylogroups and representing both pathogenic and non-pathogenic viruses – to inhibit apoptosis in infected cells. Primary human endothelial cells were infected with ANDV, HTNV, the HFRS-causing Puumala virus (PUUV) and Seoul virus, as well as the putative non-pathogenic Prospect Hill virus and Tula virus. Infected cells were then exposed to the apoptosis-inducing chemical staurosporine or to activated human NK cells exhibiting a high cytotoxic potential. Strikingly, all orthohantaviruses inhibited apoptosis in both settings. Moreover, we show that the nucleocapsid (N) protein from all examined orthohantaviruses are potential targets for caspase-3 and granzyme B. Recombinant N protein from ANDV, PUUV and the HFRS-causing Dobrava virus strongly inhibited granzyme B activity and also, to certain extent, caspase-3 activity. Taken together, this study demonstrates that six different orthohantaviruses inhibit apoptosis, suggesting this to be a general feature of orthohantaviruses likely serving as a mechanism of viral immune evasion.

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).This Review covers the role of natural killer cells in acute and chronic viral infections, with emphasis on human infections and insights from patients with primary immunodeficiencies affecting natural killer cells. It also describes the emerging data on how natural killer cells are involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.