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  • Review Article
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Reciprocal regulation between natural killer cells and autoreactive T cells

Nature Reviews Immunology volume 6, pages 751–760 (2006)Cite this article

Key Points

  • The initiation and the progression of autoimmune diseases are controlled by complex interplay between cells of the innate immune system and the adaptive immune system.

  • Emerging evidence indicates that natural killer (NK) cells, which are components of the innate immune system, and autoreactive T cells, which are components of the adaptive immune system, undergo crosstalk during the initiation and the progression of autoimmunity.

  • Individuals with genetic defects in the number or the function of NK cells are predisposed to the development of autoimmune diseases, at least in some cases. However, studies of mice that have defects in NK-cell number or function, or mice that have been treated with NK-cell-depleting antibodies, have shown that NK cells can have either a beneficial or a deleterious influence on the generation of autoreactive T-cell responses, depending on the particular animal model that is used, the stage (initiation versus progression) of the disease that is studied and the experimental procedures that are used.

  • On the one hand, NK cells might promote the generation of autoreactive T cells by producing pro-inflammatory cytokines (such as interferon-γ), activating antigen-presenting cells, providing co-stimulatory signals to T cells and/or presenting antigens directly to T cells. On the other hand, NK cells might inhibit the generation of autoreactive T cells by producing regulatory cytokines (such as interleukin-10, IL-10), lysing antigen-presenting cells or T cells, or modulating the activity of other regulatory cells (such as natural killer T cells and CD4+CD25+ regulatory T cells).

  • Humans and mice with established autoimmunity have defects in the number and the function of NK cells, a phenomenon that is known as NK-cell degeneration.

  • Recent studies have provided evidence that autoreactive T cells might promote NK-cell degeneration, in a mechanism that probably involves IL-21 production by autoreactive T cells. As such, autoreactive T cells might 'paralyse' NK cells, perhaps to avoid the disease-promoting effects of NK cells.

  • To improve our understanding of the complex interactions between NK cells and autoreactive T cells, new immunological tools (such as antibodies that can selectively deplete NK cells) and genetic tools (such as gene-knockout mice that selectively lack NK cells) need to be developed.

  • A better understanding of the interactions between NK cells and autoreactive T cells might be exploited to develop therapies that target NK cells for patients with autoimmune disease.

Abstract

The initiation and the progression of autoimmune diseases stem from complex interactions that involve cells of both the innate and the adaptive immune system. As we discuss here, natural killer (NK) cells, which are components of the innate immune system, can inhibit or promote the activation of autoreactive T cells during the initiation of autoimmunity. After they have been activated, autoreactive T cells contribute to the homeostatic contraction of NK-cell populations. The dynamic interaction between NK cells and autoreactive T cells might indicate the transition from the innate immune triggering of autoimmunity to the progressive phase of the disease. Understanding the mechanisms and signals that control the reciprocal regulation of NK cells and autoreactive T cells could have important implications for treatment in the clinic.

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Figure 1: Proposed mechanisms by which natural killer cells regulate autoreactive T cells.
Figure 2: Chemokine-guided, organ-specific recruitment of natural killer cells as a double-edged sword in inflammation and autoimmunity.
Figure 3: Hypothetical model of reciprocal regulation between natural killer cells and autoreactive T cells.
Figure 4: T cells can have divergent effects on natural killer cells.

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Acknowledgements

We thank the following: R. M. Ransohoff for collaboration and crucial advice in preparation of this Review; T. Vollmer, A. La Cava, X. Bai, D. Huang and D. Campagnolo for fruitful discussions; and R. Liu, W. Piao and P. Minick for editorial assistance. We apologize to those colleagues whose work we could not cite as a result of space constraints. Work in the authors' laboratories is supported by the Muscular Dystrophy Association (USA), the Barrow Neurological Foundation (USA) and the National Institutes of Health (USA).

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Authors and Affiliations

  1. Barrow Neurological Institute, Saint Joseph's Hospital and Medical Center, Phoenix, 85013, Arizona, USA

    Fu-Dong Shi

  2. Department of Microbiology and Immunology, Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, 37232, Tennessee, USA

    Luc Van Kaer

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  1. Fu-Dong Shi
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Correspondence to Fu-Dong Shi.

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Glossary

Negative selection

The deletion of self-reactive thymocytes, in the thymus. Thymocytes expressing T-cell receptors that strongly recognize self peptide bound to self MHC molecules undergo apoptosis in response to the signalling that results from high-affinity binding.

Type 1 diabetes

A chronic autoimmune disease that is characterized by the T-cell-mediated destruction of β-cells (which secrete insulin), in the pancreas. Patients with type 1 diabetes develop hyperglycaemia and can develop diabetes-associated complications in multiple organ systems, owing to lack of insulin. Diabetes in non-obese diabetic (NOD) mice is a model of type 1 diabetes.

Rheumatoid arthritis

A chronic systemic autoimmune disease that is mainly characterized by joint inflammation.

Multiple sclerosis

A prevalent autoimmune disease of the brain and spinal cord that is characterized by inflammation, demyelination and axonal damage. The clinical presentation of neurological deficits is highly heterogeneous and depends on the site and the extent of central-nervous-system involvement.

T helper 1 cell

(TH1 cell). CD4+ T cells are classified on the basis of the types of cytokine that they secrete. TH1 cells produce interferon-γ, lymphotoxin-α and tumour-necrosis factor, and they support cell-mediated immunity. TH2 cells produce interleukin-4 (IL-4), IL-5 and IL-13, and they support humoral immunity and downregulate TH1-cell responses. An imbalance between TH1-cell responses and TH2-cell responses is thought to contribute to the pathogenesis of various infections, allergic responses and autoimmune diseases.

Natural killer T cells

(NKT cells). A heterogeneous subset of T cells, most of which express semi-invariant T-cell receptors. In mice, NKT cells were first identified through their expression of the cell-surface molecule natural-killer-cell-associated antigen 1.1 (NK1.1; also known as NKR-P1C).

γδ T cell

A T cell that expresses a T-cell receptor consisting of a γ-chain and a δ-chain. These T cells are present mainly in the intestinal epithelium as intraepithelial lymphocytes (IELs). Although the exact function of γδ T cells (or IELs) is still unknown, it has been suggested that mucosal γδ T cells are involved in innate immune responses by the mucosal immune system.

B1 cells

A group of self-renewing, autoreactive B cells with a limited B-cell-receptor repertoire. These cells are mainly found in the peritoneal cavity and the pleural cavity.

Experimental allergic encephalomyelitis

(EAE). An animal model of multiple sclerosis. EAE can be induced in several mammalian species by immunization with myelin-derived antigens together with adjuvant. The immunized animals develop a paralytic disease that has several pathological features in common with multiple sclerosis in humans.

Collagen-induced arthritis

An animal model of rheumatoid arthritis. Collagen-induced arthritis develops in susceptible rodents and primates after immunization with cartilage-derived type II collagen.

Adjuvant

An agent that is mixed with an antigen and increases the immune response to immunization with that antigen.

Type-II C-type lectin-like molecules

Lectins are carbohydrate-binding molecules, and C-type lectins were named after their ability to bind calcium. C-type lectin-like molecules — for example, many of the natural-killer-cell receptors — are disulphide-linked homodimers that have sequence homology to C-type lectins; however, they do not bind calcium, and they often recognize proteins instead of carbohydrates. Type II lectin-like molecules are type II transmembrane proteins, for which the amino terminus is intracellular and the carboxy terminus is extracellular.

Transporter associated with antigen processing

(TAP). A molecule that translocates short peptides from the cytosol to the lumen of the endoplasmic reticulum, where these peptides can bind MHC class I molecules. TAP-deficient mice or humans have marked defects in cell-surface MHC class I expression, CD8+ T-cell development and natural killer (NK)-cell function. MHC-class-I-deficient cells are highly susceptible to lysis by wild-type NK cells, a finding that formed the basis for the 'missing-self' hypothesis of NK-cell-mediated target-cell recognition.

Systemic lupus erythematosus

(SLE). A chronic systemic autoimmune disease that is characterized by rashes, arthritis, kidney disease and central-nervous-system involvement. It is mediated by antibodies that are specific for double-stranded DNA and other nuclear antigens.

Myasthenia gravis

A chronic autoimmune disease that involves the generation of T-cell-dependent autoantibodies specific for the acetylcholine receptor. These antibodies interfere with the transmission of signals at neuromuscular junctions.

CD4+CD25+ regulatory T cell

(TReg cell). A specialized type of CD4+ T cell that can suppress the responses of other T cells. These cells provide a crucial mechanism for the maintenance of peripheral self-tolerance and are characterized by expression of CD25 (also known as the α-chain of the interleukin-2 receptor) and the transcription factor forkhead box P3 (FOXP3).

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Shi, FD., Van Kaer, L. Reciprocal regulation between natural killer cells and autoreactive T cells. Nat Rev Immunol 6, 751–760 (2006). https://doi.org/10.1038/nri1935

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