Evolutionary struggles between NK cells and viruses

Abstract

Natural killer (NK) cells are well recognized for their ability to provide a first line of defence against viral pathogens and they are increasingly being implicated in immune responses against certain bacterial and parasitic infections. Reciprocally, viruses have devised numerous strategies to evade the activation of NK cells and have influenced the evolution of NK-cell receptors and their ligands. NK cells contribute to host defence by their ability to rapidly secrete cytokines and chemokines, as well as to directly kill infected host cells. In addition to their participation in the immediate innate immune response against infection, interactions between NK cells and dendritic cells shape the nature of the subsequent adaptive immune response to pathogens.Natural killer (NK) cells contribute to the innate immune defence against tumours and microbial pathogens. They sense their environment by using a sophisticated repertoire of receptors that allows them to distinguish between normal cells and transformed cells or cells infected with intracellular pathogens 1 (BOX 1). NK cells are most abundant in the blood, liver and spleen, but they are also present in lymph nodes, and they can migrate into inflamed or tumour-bearing tissues and organs. 'Resting' mature NK cells constitutively express transcripts for certain cytokines, such as interferon-γ (IFNγ) 2 , and they contain pre-formed cytolytic mediators (granzymes and perforin), stored in intracellular granules 3 . Despite already being armed for attack, NK cells require activation by type I interferons (that is, IFNα or IFNβ) or pro-inflammatory cytokines, such as interleukin-15 (IL-15), IL-12 and IL-18, before becoming fully functional effector cells that can provide optimal host defence against infections. In many situations, dendritic cells (DCs) are probably the main source of the type I IFN and IL-12 that is necessary for NK-cell activation, and in turn, IFNγ produced by NK cells can affect the maturation and effector functions of DCs, as well as other leukocytes, including macrophages, granulocytes and other lymphocytes that are responding to the infection. In some cases, NK cells can directly recognize and respond to a cell infected with a virus, but cognate recognition of the infected cell is not absolutely required for NK cells to participate in a response because they can be activated as bystander cells simply by exposure to IFNs and cytokines in their environment. For example, culture of NK cells with IL-12 and IL-18 (or other combinations of cytokines with IL-12) is sufficient to initiate secretion of IFNγ, without requiring any deliberate engagement of the activating receptors expressed by NK cells that detect alterations in the cell surface of the infected or transformed cells. In addition, because NK cells express CD 16, an activating Fc receptor for IgG (FcγR), they can attack virus-infected cells that are coated with IgG, with specificity being contributed by the antibody. Therefore, the relative contribution of and effector mechanisms invo...

Functional role of human NK cell receptor 2B4 (CD244) isoforms

“…NK cells Introduction NK cells are a fundamental component of the innate immune system, capable of recognizing and destroying tumor cells as well as cells that have been infected by viruses or bacteria [1]. In addition to their role in innate immune responses, interactions between NK cells and dendritic cells regulate the adaptive immune response to pathogens [2]. NK cell functions are regulated by a dynamic interplay between activating and inhibitory signals transmitted by distinct classes of receptors found on their surface [3,4].…”

“…In addition to their role in innate immune responses, interactions between NK cells and dendritic cells regulate the adaptive immune response to pathogens [2]. NK cell functions are regulated by a dynamic interplay between activating and inhibitory signals transmitted by distinct classes of receptors found on their surface [3,4].…”

The extreme plasticity of killer cell Ig‐like receptor (KIR) haplotypes differentiates rhesus macaques from humans

“…They bridge the gaps between innate and adaptive immunity [1]. NK cells not only provide defence against infection [2] and cancer [3] but they are also involved with the vascularisation process during placentation, and thus contribute to reproductive success [4]. The education and activation state of the NK-cell is determined by the interactions of its receptors with their cognate ligands [5].…”

ULBP6/RAET1L is an additional human NKG2D ligand

“…Ectopic expression of NKG2D ligand leads to anticancer immune responses to transplanted tumours in mice, and the NKG2D knockout mouse has an increased susceptibility to certain types of cancer [18][19][20]. The importance of NKG2D in antiviral immune responses is illustrated by the fact that many viruses have evolved one, and sometimes multiple, mechanisms to prevent cell-surface expression of NKG2D ligand [21]. Therefore, NKG2D has been described as participating in ''stressed'' or ''damaged self'' recognition [22,23].…”

“…NKG2D ligands are significantly variable in their amino acid sequence, expression profile, domain structure, trafficking and cellular localisation, affinity for NKG2D, and interaction with viral proteins [9]. Evolutionary competition with viruses is likely to have been a significant driving force behind NKG2D ligand diversity as many viruses have developed at least one mechanism to evade NKG2D-mediated antiviral immune responses [9,21]. However, the independent and tissue-specific expression of NKG2D ligands and apparent functional adaptations to specific tissues, such as the basolateral targeting of MICA [37], suggest that different NKG2D ligands may have evolved non-redundant functions beyond a role in viral infection.…”