Natural killer cell responses during viral infections: flexibility and conditioning of innate immunity by experience
Highlights
► NK cells have antiviral and regulatory functions controlled by innate receptors discriminating infected cells. ► Receptor ligands, stress and MHC1-like molecules, are often targeted by viruses. ► Inhibitory receptors mediate “missing self” recognition. ► Activating receptors recognize altered self, promote proliferation and protracted maintenance of experienced NK cells. ► Innate cytokines further regulate NK cell responses. ►
Introduction
Natural killer (NK) cells were originally described as lymphocytes of the innate immune system capable of eliminating tumor and infected cells without prior antigen exposure [1]. This was quickly followed by the demonstration of the first NK cell activating receptor, the receptor for Fc portions of immunoglobulin molecules, CD16, and the ability of NK cells to interface with these components of adaptive immunity to mediate antibody-dependent cellular cytotoxicity (ADCC) [1]. NK cells are now known to be proficient at many important tasks [2] but are still best appreciated for their non-redundant roles in defense against some viruses. Plentiful studies in the mouse and human demonstrate NK cell-dependent protective effects during infections with coxsackievirus, human immunodeficiency virus (HIV), hepatitis C virus (HCV), influenza virus, and poxvirus, but most importantly herpesviruses [3, 4, 5]. The mechanisms for delivery of their direct antiviral effects include killing of infected target cells and production of interferon γ (IFNγ), and absence of the cells before infection increases early replication of viruses sensitive to NK cell-mediated defense [5, 6]. There is compelling evidence that their antiviral effects are regulated by a repertoire of germ-line encoded NK cell receptors (NKRs) recognizing ligands on virus-infected cells and by innate cytokine responses induced during infections. Despite extensive work in many laboratories, the molecular details of the pathways controlling NK cell responses have been elusive because of the many closely related inhibitory and activating receptors as well as the pleotropic and sometimes paradoxical effects of cytokines.
Exciting new molecular characterization of the NK cell receptor–ligand pairs and cytokine effects modified in response to viral infections are filling in significant gaps in knowledge. In addition to providing details on the pathways controlling NK cell contributions to defense and those protecting from potential immune-mediated pathology, the new information is revealing unexpected flexibility in NK cell responses based on experience-induced ‘conditioning’. In particular, much progress has been made in identifying infection-induced changes in the expression of ligands for NK cell activating and inhibitory receptors, in the role for activating receptors in expanding and sustaining NK cell subsets for extended periods, and in their responses to innate cytokines. The observations have implications for understanding the regulation of NK cell functions not only during early innate responses to viruses but also during periods overlapping with adaptive and long-term immunity. Moreover, they suggest that individual variations in resistance to infection are based on experiences as well as genes.
Section snippets
NK cell receptors
The NK cell receptors delivering inhibitory signals were first appreciated because of their ability to receive negative ‘self’ signals from class 1 major histocompatibility (MHC1) molecules expressed on normal tissues [7, 8]. It is now clear that there are complex groups of NKRs with different genetic and structural characteristics, representatives of both inhibitory and activating receptor in each group, and individual NK cells expressing combinations of both inhibitory and activating
Viral infection-induced receptor–ligand pairs in the mouse
Some activating NKRs are able to directly recognize virus-infected cells. For example, Ly49H from C57BL/6 resistant mice was the first NKR demonstrated to be a viral resistance gene (cmv1) and mediates its effects by recognizing the mouse cytomegalovirus (MCMV) m157 viral protein, which is highly homologous to MHC1 and expressed only on MCMV-infected cells [20, 21, 22, 23] (Figure 2; Table 1). Ligation of Ly49H by m157 results in the release of cytolytic granules, cytokines, and chemokines, as
Viral infection-induced receptor–ligand pairs in the human
Human viral infections are infrequently studied in the acute phase owing to logistical difficulties in obtaining samples. However, there are some informative studies. Peripheral blood NK cell numbers are reduced in the acute phase of influenza H1N1 infection and in acute HCV infection the numbers of cytotoxic CD56dim NK cells are also reduced [40, 41•]. Conversely, in acute Puumala hantavirus infection, NK cell numbers are elevated up to two-fold [42••]. The expansion is associated with
NK receptors for proliferation, maintenance and function following infection
Early interest in NK receptors was driven by efforts to understand the regulation of innate NK cell-mediated killing of virus-infected target cells, but delivery of activating signals can also lead to proliferation. Because NK cells are relatively abundant in many tissues, and high proportions basally express or are induced by cytokines to express different activating receptors, the advantages of NK cell proliferative responses have remained obscure. Interestingly, however, NK cells numbers or
Induction of innate cytokines and regulation of NK cell responses
The importance of innate cytokines in regulating NK cell functions was first realized with the demonstration that the antiviral type 1 IFNs, IFNαβ, were potent inducers of elevated NK cell-mediated lysis [1]. Since that time, it has becomes clear that many viral infections induce complex innate pro-inflammatory cytokine cascades, including in addition to type 1 IFNs, biologically active IL-12p70, IL-18 and IL-15 [97]. In terms of overall kinetics of production, cellular sources, and
Conclusions
In summary, although NK cells were first proposed to be key mediators of innate immune responses to viral infections, it is now clear that there are many mechanisms in place to dramatically regulate their functions at the very earliest times after infections as well as to support their continued availability through times overlapping with adaptive immunity. A profound flexibility in responding to virus-induced cytokines and changes in the expression of ligands for activating and inhibitory
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors apologize to their colleagues whose work was not cited owing to space limitations. Research in the authors’ laboratories is funded by the Canadian Institutes of Health Research, Canada, The Wellcome Trust, UK, and the National Institutes of Health, USA. They thank their many current and past laboratory members for their contributions to the work reviewed here.
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2022, Human ImmunologyCitation Excerpt :Tissue resident macrophages and dendritic cells (DCs) are considered as first responders [67] which recognize viral infected cells expressing pathogen associated molecular patterns (PAMPs) through germline-encoded pattern recognition receptors (PRRs) [68]. NK cells are also other members of innate immune system which play a key role in the host’s immune defense against pathogens preventing the establishment of infection and the viral spreading through the body [69]. So far, several studies in mice models or humans with compromised NK cell activity or lacking functional NK cells have highlighted the crucial role of these cells against viral infection [70].
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2021, Cell ReportsCitation Excerpt :NK cell activity against target cells is regulated by the balance of germline-encoded activating versus inhibitory receptors, and despite multiple viral evasion strategies, NK cells are particularly potent in restricting herpesvirus infections (Mancini and Vidal, 2020). They contribute to antiviral immunity via cytokine production, such as interferon (IFN)-γ in response to interleukin (IL)-12, and direct killing of infected cells induced by type I IFNs (Vidal et al., 2011). In order to exert these antiviral immune responses, NK cells often require an IL-15-and IL-18-dependent priming step in secondary lymphoid tissues, reminiscent of CD8+ T cell priming (Chaix et al., 2008; Lucas et al., 2007).