Elsevier

Journal of Autoimmunity

Volume 39, Issue 3, September 2012, Pages 206-215
Journal of Autoimmunity

Review
Regulatory NK cells in autoimmune disease

https://doi.org/10.1016/j.jaut.2012.05.006Get rights and content

Abstract

As major components of innate immunity, NK cells not only exert cell-mediated cytotoxicity against tumor cells or infected cells, but also act to regulate the function of other immune cells by secretion of cytokines and chemokines, thus providing surveillance in early defense against viruses, intracellular bacteria and cancer cells. However, the effector function of NK cells must be exquisitely controlled in order to prevent inadvertent attack against self normal cells. The activity of NK cells is defined by integration of signals coming from inhibitory and activation receptors. Inhibitory receptors not only distinguish healthy from diseased cells by recognize self-MHC class I molecules on cell surfaces with “missing-self” model, but also provide an educational signal that generates functional NK cells. NK cells enrich in immunotolerance organ and recent findings of different regulatory NK cell subsets have indicated the unique role of NK cells in maintenance of homeostasis. Once the self-tolerance is broken, autoimmune response may occur. Although data has demonstrated that NK cells play important role in autoimmune disorders, NK cells seemed to act as a two edged weapon and play opposite roles with both regulatory and inducer activity even in the same disease. The precise role and regulatory mechanisms need to be further determined. In this review, we focus on recent research on the association of NK cells and antoimmune diseases, particularly the genetic correlation, the immune tolerance and misrecognition of NK cells, the regulatory function of NK cells, and their potential role in autoimmunity.

Highlights

► There is genetic correlation of autoimmune diseases with NK cell receptor/ligands. ► NK cells play important role in maintenance of homeostasis. ► Misrecognition of NK cells may contribute to pathogenesis of autoimmune diseases. ► NK cells seemed to act as a two edged weapon in autoimmune diseases.

Introduction

NK cells are major components of innate immunity and provide surveillance in early defense against viruses, intracellular bacteria and cancer cells [1], [2]. They not only exert cell-mediated cytotoxicity against tumor cells or infected cells, but also act to regulate the function of other immune cells by secretion of cytokines and chemokines [3], [4], [5]. NK cells express multiple activating and inhibitory receptors on their surfaces. The activity of NK cells is now understood to be controlled by a dynamic signal balance between activating and inhibitory receptors engaged upon interaction with ligands presented on target cell surfaces [6], [7], [8]. NK cell function goes beyond cytotoxicity and includes a regulatory component in both innate and adaptive immune responses [4], [5], [9]. In particularly, they may prime, influence and regulate the activities of adaptive immune responses, including T cells and dendritic cells (DCs), via cytokine secretion or cell-to-cell contact [4], [5], [9]. This interaction implies the crucial role of NK cells for immunity to infections and tumors. However, these effector responses must be exquisitely controlled in order to prevent attack against self normal cells. Indeed, accumulating data have demonstrated that NK cells play important roles in autoimmune disorders. However, NK cells act as a two edged weapon in autoimmune diseases and may play opposite roles with both regulatory and inducer activity even in the same disease [10], [11]. The role NK cells or their subsets play in autoimmune diseases may involve the tissue cells who become targets of NK cells and be different at various stages of a corresponding autoimmune disease. In this review, we focus on recent research on the association of NK cells and antoimmune diseases, particularly the genetic correlation, the immune tolerance and misrecognition of NK cells, and the regulatory function of NK cells and their potential role in autoimmunity.

Section snippets

Genetic correlation of autoimmune diseases with NK cells

NK cells express germline-encoded receptors including inhibitory and activation receptors. In humans, the predominant NK cell receptors are the killer-cell immunoglobulin (Ig)-like receptors (KIRs). In mice, the major NK cell receptors are C-type lectin-like molecules belonging to the Ly49 family. Both human and mouse NK cells also express a conserved lectin-like heterodimeric receptor CD94 coupled with members of the NKG2 family. The activity of NK cells is defined by integration of signals

NK cells in immune tolerance

NK cells play major roles in defense of malignancy and infection diseases by direct cytolysis of target cells and secretion of cytokines. These effector responses must be controlled to avoid inadvertent damage to normal cells. Inhibitory receptors, in particular MHC class I-specific receptors, are considered as a predominant mechanism responsible for NK cell self-tolerance. Recently, other mechanisms, such as NK cell education and activating NK cell receptors, also exert necessary effect. The

Misrecognition and reversal of NK cells-mediated autoimmunity

As described above, NK cell inhibitory receptors not only protect normal cells from the attack by recognizing MHC-specific ligands, but also confer NK cells function. On the other hand, various activating receptors expressed on surface of NK cells exert critical roles in attacking tumor and infected cells. Under certain condition, the activating signaling can overcome the inhibition effect from inhibitory receptors. Some activating receptors, such as NKG2D, recognize induced protein ligands

The protective role of NK cells in autoimmune diseases

The decreased NK cell frequency and impaired NK cell cytotoxicity observed in a variety of autoimmune diseases implies a protective role of NK cells in controlling autoimmunity. Natural killer cells may limit autoimmune responses by inhibiting the proliferation and activation of auto-reactive T lymphocytes, hampering the activation of macrophages or by killing immature DCs. Evidence has shown that NK2 subsets exert negative regulatory characters and suppress the function of auto-reactive T

Concluding remarks

Although emerging evidence has shown that the regulatory effect of NK cells play major roles both in maintaining immune homeostasis and in mediating the pathogenesis of autoimmunity, the precise role and regulatory mechanisms is an enigma. Further investigation should dissect the role of distinct NK cell subsets in different autoimmune diseases, and in various stages of diseases. One needs to focus on the influence of the local microenvironment on the behavior and function of NK cells. Improved

Funding

This work was supported by the Ministry of Science & Technology of China (973 Basic Science Project 2012CB519004, 2009CB522403), Natural Science Foundation of China (#91029303, #30730084, #30911120480, #31021061, #90713033, #30901307), National Science & Technology Major Projects (2012ZX10002-014) and National Institutes of Health Grant DK39588.

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