Organ-specific features of natural killer cells

Abstract

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.

Figure 1. Unique effector properties of NK cells in the liver.

a | CC-chemokine ligand 2 (CCL2), CCL3, CXC-chemokine ligand 10 (CXCL10) and sphingosine-1-phosphate (S1P) derived from Kupffer cells and other hepatic cells attract natural killer (NK) cells to the inflamed liver. b | Hepatic NK cells reside in distinctive, thin-walled sinusoids, where Kupffer cells and other lymphocytes are also located. Hepatic NK cells face the challenging task of balancing immunity to multiple hepatotropic viruses and bacteria with tolerance to food and self antigens. In the steady state, commensal-derived lipoteichoic acid (LTA) and lipopolysaccharide (LPS) that arrive in the liver from the gut through the portal vein ligate Toll-like receptor 2 (TLR2) and TLR4, respectively, on Kupffer cells, triggering the release of interleukin-10 (IL-10). IL-10 in turn renders NK cells hyporesponsive to IL-12 and IL-18 and promotes tolerance in the liver. In addition, expression of the inhibitory receptor natural killer group 2, member A (NKG2A) is increased, whereas expression of the activating receptor LY49 is decreased on NK cells. c | During viral infection, double-stranded RNA (dsRNA) ligates TLR3 and triggers Kupffer cells to release IL-6 and IL-18, which in turn activate NK cells and boost their killing activity. This is reflected by the phenotype of hepatic NK cells, which is characterized by the expression of high levels of TNF-related apoptosis-inducing ligand (TRAIL), perforin and granzymes, and a lack of LY49. Activated hepatic NK cells can lyse hepatocytes or stellate cells via TRAIL-dependent pathways during hepatitis B virus infection or fibrosis, respectively. Thus, Kupffer cells appear to have a dual role in shaping hepatic NK cell phenotype and function. Hepatic NK cells are also subjected to the influence of interferon-γ (IFNγ) released by natural killer T (NKT) cells. Hepatic NK cells can acquire memory to antigens derived from influenza virus, vesicular stomatitis virus and HIV-1 (not shown). CCR, CC-chemokine receptor; CXCR, CXC-chemokine receptor; S1PR, S1P receptor.

Figure 2. The brain alters NK cell phenotypes and functions.

The entry of lymphocytes into the central nervous system (CNS) is normally shielded by the blood–brain barrier, which becomes compromised in several pathological circumstances. Natural killer (NK) cells are recruited to the inflamed brain by CX₃C-chemokine ligand 1 (CX₃CL1) produced by neurons. Brain-specific cell types and neurotransmitters alter the features of NK cells that migrate from the periphery. An array of cytokines, growth factors and neurotransmitters produced by microglial cells, astrocytes and neurons can influence NK cell activation and proliferation. The chemokine CC-chemokine ligand 3 (CCL3) attracts NK cells to the site of inflammatory foci. After acquiring new features, brain-resident NK cells lose tolerance to microglial cells, suppress pathogenic, myelin-reactive T helper cells and significantly attenuate the intensity of local inflammatory and autoimmune responses. NK cells also kill neurons infected by herpes simplex virus. In addition, mediators derived from neurons, microglial cells and astrocytes and multidirectional cellular interactions may influence NK cell tolerance and function. The combined effects of soluble factors and cellular interactions, as well as the timing of the immune response, may dictate NK cell activity in the CNS. ACh, acetylcholine; BDNF, brain-derived neurotrophic factor; CXCL10, CXC-chemokine ligand 10; EGF, epidermal growth factor; IFNβ, interferon-β; IL, interleukin; M-CSF, macrophage colony-stimulating factor; NGF, nerve growth factor; NO, nitric oxide; PGE2, prostaglandin E2; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor.