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).
Natural killer (NK) cells are innate lymphocytes that participate in immune responses against virus-infected cells and tumors. As a countermeasure, viruses and tumors employ strategies to evade from ...NK cell-mediated immunosurveillance. In this review, we examine immune evasion strategies employed by viruses, focusing on examples from human cytomegalovirus (HCMV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We explore selected viral evasion mechanisms categorized into three classes: (1) providing ligands for the inhibitory receptor NKG2A, (2) down-regulating ligands for the activating receptor NKG2D, and (3) inducing the immunosuppressive cytokine transforming growth factor (TGF)-β. For each class, we draw parallels between immune evasion by viruses and tumors, reviewing potential opportunities for overcoming evasion in cancer therapy. We suggest that in-depth investigations of host-pathogen interactions between viruses and NK cells will not only deepen our understanding of viral immune evasion but also shed light on how NK cells counter such evasion attempts. Thus, due to the parallels of immune evasion by viruses and tumors, we propose that insights gained from anti-viral NK cell responses may serve as valuable lessons that can be leveraged for designing future cancer immunotherapies. This article is protected by copyright. All rights reserved.
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.
The discovery that NK cells are able to specifically recognize cells lacking the expression of self‐MHC class I molecules provided the first insight into NK cell recognition of tumour cells. It ...started a flourishing field of NK cell research aimed at exploring the molecular nature of NK cell receptors involved in tumour cell recognition. While much of the important early work was conducted in murine experimental model systems, studies of human NK cells rapidly followed. Over the years, human NK cell research has swiftly progressed, aided by new detailed molecular information on human NK cell development, differentiation, molecular specificity, tissue heterogeneity and functional capacity. NK cells have also been studied in many different diseases aside from cancer, including viral diseases, autoimmunity, allergy and primary immunodeficiencies. These fields of research have all, indirectly or directly, provided further insights into NK cell‐mediated recognition of target cells and paved the way for the development of NK cell‐based immunotherapies for human cancer. Excitingly, NK cell‐based immunotherapy now opens up for novel strategies aimed towards treating malignant diseases, either alone or in combination with other drugs. Reviewed here are some personal reflections of select contributions leading up to the current state‐of‐the‐art in the field, with a particular emphasis on contributions from our own laboratory. This review is part of a series of articles on immunology in Scandinavia, published in conjunction with the 50th anniversary of the Scandinavian Society for Immunology.
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.
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.
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 and has since become a global pandemic. Pathogen-specific Abs are ...typically a major predictor of protective immunity, yet human B cell and Ab responses during COVID-19 are not fully understood. In this study, we analyzed Ab-secreting cell and Ab responses in 20 hospitalized COVID-19 patients. The patients exhibited typical symptoms of COVID-19 and presented with reduced lymphocyte numbers and increased T cell and B cell activation. Importantly, we detected an expansion of SARS-CoV-2 nucleocapsid protein-specific Ab-secreting cells in all 20 COVID-19 patients using a multicolor FluoroSpot Assay. Out of the 20 patients, 16 had developed SARS-CoV-2-neutralizing Abs by the time of inclusion in the study. SARS-CoV-2-specific IgA, IgG, and IgM Ab levels positively correlated with SARS-CoV-2-neutralizing Ab titers, suggesting that SARS-CoV-2-specific Ab levels may reflect the titers of neutralizing Abs in COVID-19 patients during the acute phase of infection. Last, we showed that IL-6 and C-reactive protein serum concentrations were higher in patients who were hospitalized for longer, supporting the recent observations that IL-6 and C-reactive protein could be used as markers for COVID-19 severity. Altogether, this study constitutes a detailed description of clinical and immunological parameters in 20 COVID-19 patients, with a focus on B cell and Ab responses, and describes tools to study immune responses to SARS-CoV-2 infection and vaccination.
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.
Natural killer (NK)–cell recognition of infected or neoplastic cells can induce cytotoxicity and cytokine secretion. So far, it has been difficult to assess the relative contribution of multiple ...NK-cell activation receptors to cytokine and chemokine production upon target cell recognition. Using Drosophila cells expressing ligands for the NK-cell receptors LFA-1, NKG2D, DNAM-1, 2B4, and CD16, we studied the minimal requirements for secretion by freshly isolated, human NK cells. Target cell stimulation induced secretion of predominately proinflammatory cytokines and chemokines. Release of chemokines MIP-1α, MIP-1β, and RANTES was induced within 1 hour of stimulation, whereas release of TNF-α and IFN-γ occurred later. Engagement of CD16, 2B4, or NKG2D sufficed for chemokine release, whereas induction of TNF-α and IFN-γ required engagement of additional receptors. Remarkably, our results revealed that, upon target cell recognition, CD56dim NK cells were more prominent cytokine and chemokine producers than CD56bright NK cells. The present data demonstrate how specific target cell ligands dictate qualitative and temporal aspects of NK-cell cytokine and chemokine responses. Conceptually, the results point to CD56dim NK cells as an important source of cytokines and chemokines upon recognition of aberrant cells, producing graded responses depending on the multiplicity of activating receptors engaged.
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