Regulation of natural killer cell activity

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Information regarding the role of natural killer (NK) cells in the response to viruses, intracellular bacteria and parasites continues to emerge. NK cells can directly lyse infected cells, secrete cytokines and interact with dendritic cells to drive the adaptive immune response. There are a large number of activating and inhibitory receptors that govern NK cell activity. Recent studies have revealed how signals are transmitted and integrated from the variety of receptors, how particular receptors influence NK development and functional status, and how NK cells access lymph nodes and sites of infection. The potential for NK cells to exhibit specific and memory-like responses has begun to blur the ‘innate’ definition of NK cells.

Introduction

Natural killer (NK) cells are an important component of innate resistance to viruses, bacteria, certain parasites and tumors, which use cytolytic granules and cytokine production to mediate their effector functions. NK cells also interface with adaptive immunity by stimulating dendritic cells (DCs) and by promoting T-cell responses. Originally designated as null lymphocytes that lack known lymphocyte surface markers, we now know that these cells express many distinct receptor systems to recognize and respond to pathogens. Moreover, NK receptor polymorphism is linked to susceptibility to infectious diseases, autoimmunity and fertility (reviewed in [1]). As NK recognition of pathogens was recently covered in this journal [2], in this article we will focus on how receptors regulate NK cell activation and localization.

Section snippets

NK activating and inhibiting receptors

The term ‘NK activating receptor’ generally refers to those receptors that trigger release of cytolytic granules and typically induce cytokine production [3]. Established activating receptors on NK cells include the natural cytotoxicity receptors (e.g. NKp30, NKp44 and NKp46), NKG2D, NKRP1, CD16, and activating killer cell Ig-like receptors in human (activating KIRs) or activating Ly49s in mouse (for abbreviations and classification of molecules throughout the review, please see Box 1). Ligands

Intracellular signaling pathways

Generally, activating receptors use a similar scheme to that of antigen-specific and Fc receptors (Figure 1) by forming complexes with adaptor proteins that have ITAM sequences (DAP12, Fcγ or the ζ chain), using src and syk family kinases to instigate the process, producing calcium fluxes and requiring cytoskeletal remodeling to induce degranulation. The diversity of NK activating receptors is paralleled in the intracellular signaling pathways. The emphasis of late has been to clarify the

NK cell lineage and repertoire development

Understandably our knowledge of NK cell development and repertoire formation has lagged far behind that of other lymphocytes. Using knockout mice and in vitro differentiation assays, a similar scheme is emerging for both human and mouse NK cells in terms of the transcription factors, stromal cell interactions, growth factors and cytokines involved in differentiating NK cells from lymphoid progenitors to immature and mature NK stages [28]. A new development in this area is the ability to mature

NK cell trafficking

The presence of NK cells at infected sites is relevant to both the innate immune response through direct antiviral effects and the adaptive immune response by interacting with DCs [54]. NK cells are resident in several nonlymphoid organs such as liver and lung and are capable of rapidly displaying effector function upon stimulation (reviewed in [55]). Although the role of NK cells as key players early in an immune response is accepted, the details about NK cell proliferation and trafficking in

NK memory and hapten specificity

NK cells are classified as innate cells, implying that their response to re-exposure with a particular pathogen will be of the same magnitude and speed as the response to the first exposure; however, an intriguing story has emerged regarding the ability of NK cells to mediate contact hypersensitivity reactions [73••]. In this model, NK cells appear to have the surprising ability to discriminate haptens and possess a form of memory. The activity requires NKG2D and resides specifically within the

Conclusions

Our understanding of the role of NK cells in microbial and tumor responses continues to grow, as does our understanding of the many distinct receptor systems that govern their activation and how receptor variability within the population contributes to disease resistance. No longer the simple null cell, NK cells appear to undergo developmental processes to ensure self-tolerance, encompass subsets that have discrete functions and tissue localization, and perhaps even provide memory. Future

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors are supported by the Canadian Institutes for Health Research and the Alberta Heritage Foundation for Medical Research.

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