Elsevier

Clinical Immunology

Volume 130, Issue 1, January 2009, Pages 16-26
Clinical Immunology

REVIEW
NK and NKT cells in liver injury and fibrosis

https://doi.org/10.1016/j.clim.2008.08.008Get rights and content

Abstract

The innate immune mechanisms of the liver represent an important first line of defense against bacterial products, toxins, and food antigens coming from the intestine. Natural Killer (NK) and Natural Killer T cells (NKT) are components of the innate immune system with increased presence in the liver compared to other organs and have been reported to participate in the inflammatory processes during hepatic diseases. However significant confusion has been noted in this field mainly due to changes in the characterization of these cells as new knowledge accumulates and due to differences in the approaches used for their study. Both cell types can mediate hepatic injury in several models but studies in human liver diseases have not managed to fully explain their functions. However accumulating evidence supports an antifibrotic role of NK cells mainly via an inhibitory effect on hepatic stellate cells by inducing apoptosis and via production of interferon-gamma. Therefore, downregulation of NK cells during most types of liver injury may facilitate liver fibrosis. Data about the role of NKT cells in liver fibrosis are limited. This review will summarize the studies about the role of NK and NKT cells in liver diseases with a special interest in hepatic injury and liver fibrosis.

Introduction

The liver, with its strategic position between the intestine and the systemic circulation is continuously exposed to bacterial products, toxins, and food antigens. Therefore, well regulated innate immune functions are needed for effective defense against pathogenic agents while avoiding induction of destructive immune responses [1]. Natural Killer (NK) and Natural Killer T cells (NKT) are important components of the innate immune response [2]. They are present in increased proportion in the liver with respect to other lymphocyte populations. The role of NK and NKT cells in human liver diseases, liver injury models and in in vitro studies has often been a field of controversy and conflicting information. The aim of this review was to present the studies about the role of NK and NKT cells in liver diseases with a special interest in hepatic injury and liver fibrosis.

Section snippets

NK cells

NK cells are cytotoxic large granular lymphocytes (LGL) that represent a fundamental component of the innate immune system. They are derived from CD34+ hematopoietic stem cells [3] and once released, comprise roughly 5––20% of lymphocytes in the spleen, liver, and peripheral blood and are present at lower frequencies in the bone marrow, thymus, and lymph nodes [4]. NK cells do not express T-cell antigen receptors (TCR) and the pan-T marker CD3 but are CD56+CD3− [5] and are further classified to

NKT cells

Natural killer T (NKT) cells are a unique but heterogeneous group of T cells that were originally characterized in mice as cells that express both a TCR and NK1.1 (CD161c) [30]. More recently NKT cells have been defined as cells that nearly always have an invariant Vα14-Jα18 (Vα24-Jα18 in humans) rearrangement and reactivity to the glycosphingolipid α-galactosylceramide (α-GalCer) when presented by the MHC class I-like molecule CD1d that presents hydrophobic/lipid antigens [31]. However several

NK and NKT cells in liver and liver injury

Although the rationale behind NK and NKT liver tropism has obvious functional implications the underlying mechanisms have not been elucidated [4], [32], [33], [34], [48]. Homing of NKT cells to the liver has been reported to be leukocyte function-associated antigen 1 (LFA-1) dependent and surprisingly NK cell but not KC dependent [35], while local lymphopoesis of hepatic haemopoetic stem cells to NK/NKT cells has also been suggested [49].

Antigen presenting cells seem to be important for NK and

NK and NKT cells in human liver diseases

Studies of NK and NKT cells using peripheral blood cells or intrahepatic cells have been characterized by conflicting results. Part of this confusion was caused by the use of different markers to identify these cells in different studies. This is mostly due to the changes during the last 20 years on the surface markers that are considered characteristic for these cells (i.e. changes in NKT characterization) and the “resourceful” use of markers in some studies. Several reports referring to NK

NK cells

Accumulated evidence support the concept that NK cells play a protective role during induction of fibrosis. This was first reported in thioacetamide (TAA) treated rats where NK cell numbers and cytotoxic activity were found to be lower in cirrhotic rats compared to control rats, a condition that could be reversed by IFN-α administration [122] or N-acetylcysteine [48] although data about the effect of these treatment on the progression of fibrosis were not provided.

In Schistosoma mansoni-driven

Conclusions/perspectives

The liver has increased NK and NKT cells relative to the peripheral blood. NK and NKT cells modulate the activity of experimental models of liver injury and fibrosis, and probably have similar roles in human liver diseases. Although new studies will continue to define the role of these cells in liver diseases, the most definitive results to date demonstrate that NK cells inhibit liver fibrosis by inducing apoptosis in activated HSC and by secreting antifibrotic factors such as interferon γ.

Acknowledgments

George Notas is supported by a research fellowship kindly provided by the Hellenic Association for the Study of the Liver, David A. Brenner is supported by grants from the NIH.

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