Journal Article

Organ-specific features of natural killer cells

La Cava, Antonio, Van Kaer, Luc, Ljunggren, Hans-Gustaf, Shi, Fu-Dong

2011

Overview

Key Points Natural killer (NK) cells can be swiftly mobilized by danger signals and are among the earliest arrivals in target organs of disease. However, the role of NK cells in regulating inflammatory responses is far from completely understood in different organs. It is often complex and sometimes paradoxical. The phenotypes and functions of NK cells in the liver, mucosal tissues, uterus, pancreas, joints and brain are influenced by the unique cellular interactions and the local microenvironment within each organ. Hepatic NK cells exhibit an activated phenotype with high levels of cytotoxic effector molecules. These cells have been implicated in promoting liver injury and inhibiting liver fibrosis and regeneration. The liver is also enriched in NK cells with memory-like adaptive immune features. NK cells are detected in healthy lymphoid tissues of the lung, skin and gut, and are recruited to these tissues during infection or inflammation. In the gastrointestinal tract, classical NK cells and a variety of innate lymphoid cells, such as the family of lymphoid tissue-inducer (LTi) cells, are likely to have crucial roles in controlling inflammatory responses. NK cells represent the major lymphocyte subset in the pregnant uterus, with a unique phenotype resembling an early developmental state. Emerging evidence indicates that these cells play a crucial part in mediating the uterine vascular adaptations to pregnancy and promoting the maintenance of healthy pregnancy. In non-obese diabetic (NOD) mice, NK cells are recruited early to the pancreas, become locally activated and then adopt a hyporesponsive phenotype. Although NK cells have a pathogenic role in the natural progression of diabetes in NOD mice, they contribute to diabetes protection induced by complete Freund's adjuvant and to islet allograft tolerance induced by co-stimulatory blockade. NK cells in the inflamed joint uniquely express receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), which promote osteoclast differentiation. Although NK cells have a pathogenic role in collagen-induced arthritis in mice, they are also crucial for protection against antibody-induced arthritis mediated by CpG oligonucleotides. Studies in a mouse model of multiple sclerosis have shown that NK cells arrive in the central nervous system (CNS) before pathogenic T cells and have a protective role in the development of CNS inflammation, probably by killing CNS-resident microglia that prime effector T cells. During evolution, different organs might have evolved distinct ways to recruit and influence the effector functions of NK cells. Once we understand these mechanisms, the next challenge will be to exploit this information for harnessing NK cells to develop prophylactic and therapeutic measures against infectious agents, tumours and inflammatory diseases. Each tissue in our body contains a unique microenvironment that can differentially shape immune reactivity. In this Review article, Shi et al . describe how organ-specific factors influence natural killer cell homing and phenotype, and discuss the local molecular and cellular interactions that determine the protective or pathogenic functions of natural killer cells in the different tissues. Natural killer (NK) cells can be swiftly mobilized by danger signals and are among the earliest arrivals at target organs of disease. However, the role of NK cells in mounting inflammatory responses is often complex and sometimes paradoxical. Here, we examine the divergent phenotypic and functional features of NK cells, as deduced largely from experimental mouse models of pathophysiological responses in the liver, mucosal tissues, uterus, pancreas, joints and brain. Moreover, we discuss how organ-specific factors, the local microenvironment and unique cellular interactions may influence the organ-specific properties of NK cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/1619/554/383 / 631/250/256 / Animal models / Animals / Arthritis / Autoimmunity / Biomedical and Life Sciences / Biomedicine / Bone marrow / Brain / Brain - cytology / Brain - immunology / Care and treatment / Cell Communication - immunology / Cell differentiation / Cells / Central nervous system / Cerebrospinal fluid / Chemokines / Cytokines / Cytokines - immunology / Cytokines - metabolism / Cytotoxicity / Cytotoxicity, Immunologic / Development and progression / Diabetes / Diabetes mellitus / Disease Models, Animal / Female / Gastrointestinal tract / Genotype & phenotype / Health aspects / Hepatocytes / Hospitals / Humans / Immunological memory / Immunological tolerance / Immunology / Inflammation / Inflammation - immunology / Inflammation - pathology / Inflammatory diseases / Intestinal Mucosa - cytology / Intestinal Mucosa - immunology / Joint diseases / Joints - cytology / Joints - immunology / Killer cells / Killer Cells, Natural - cytology / Killer Cells, Natural - immunology / Ligands / Liver / Liver - cytology / Liver - immunology / Lymphocytes / Lymphocytes T / Lymphoid tissue / Medicine / Mice / Mice, Transgenic / Microenvironments / Microglia / Mucosa / Multiple sclerosis / Natural killer cells / Nervous system / Oligonucleotides / Organ Specificity - immunology / Osteoclastogenesis / Pancreas / Pancreas - cytology / Pancreas - immunology / Pancreatic islet transplantation / Phenotypes / Physiological aspects / Pregnancy / Receptors, Antigen, T-Cell - immunology / Receptors, Antigen, T-Cell - metabolism / Receptors, Cytokine - immunology / Receptors, Cytokine - metabolism / Regeneration / review-article / Signal Transduction - immunology / Skin / Tissues / Uterus / Uterus - cytology / Uterus - immunology