More than Decoration: Roles for Natural Killer Group 2 Member D Ligand Expression by Immune Cells

Abstract

The activating immune receptor natural killer group 2 member D (NKG2D), which is expressed by natural killer cells and T cell subsets, recognizes a number of ligands expressed by “stressed” or damaged cells. NKG2D has been extensively studied for its role in tumor immunosurveillance and antiviral immunity. To date, the majority of studies have focused on NKG2D-mediated killing of target cells expressing NKG2D ligands. However, with a number of reports describing expression of NKG2D ligands by cells that are not generally considered stressed, it is becoming clear that some healthy cells also express NKG2D ligands. Expression of these ligands by cells within the skin, intestinal epithelium, and the immune system suggests other immune functions for NKG2D ligand expression in addition to its canonical role as a “kill me” signal. How NKG2D ligands function in this capacity is just now starting to be unraveled. In this review, we examine the expression of NKG2D ligands by immune cells and discuss current literature describing the effects of this expression on immunity and immune regulation.

MICAgen Mice Recapitulate the Highly Restricted but Activation-Inducible Expression of the Paradigmatic Human NKG2D Ligand MICA

“…Splenic myeloid cells (CD11b + Gr1 + ) showed a substantial MICA expression ( Figure 4B) in line with previous reports of MICA expression by human myeloid cells (12,35). Previous in vitro studies reported an induced MICA surface expression upon activation of human leukocytes (11)(12)(13)(14)35). Hence, we wondered whether such an activation-induced MICA expression is recapitulated by MICAgen splenocytes.…”

“…Infection of human cells with various types of viruses, including herpesviruses and adenoviruses, strongly induces NKG2DL expression, which often is counteracted by NKG2DL-specific viral immunoevasins (7)(8)(9)(10). Also, activation of hematopoietic cells can induce a pronounced surface expression of NKG2DLs (11)(12)(13), which has been suggested to contribute to the modulation and control of immune responses (11,14). A functional relevance of NKG2DLs has also been implicated in many different autoimmune diseases (15).…”

Lipoteichoic Acid Is Involved in the Ability of the Immunobiotic Strain Lactobacillus plantarum CRL1506 to Modulate the Intestinal Antiviral Innate Immunity Triggered by TLR3 Activation

“…We demonstrated previously that L. plantarum CRL1506 reduced the TLR3-induced small intestinal injury in mice by regulating the production of pro-inflammatory cytokines and the interaction of IECs with IELs (11) (Figure 9). Cell-cell interaction between IECs and IELs is essential as a first line of defense against viruses (45)(46)(47). In the context of viral infection, the cell death program of IECs is regulated by their upregulation in the expression of IL-15, which is a cytokine capable of stimulating the activation of CD3 + NK1.1 + IELs and inducing perforinmediated killing of virus-infected epithelial cells (46).…”

NKG2D Ligands–Critical Targets for Cancer Immune Escape and Therapy

“…NKG2D and its ligands are therefore key proteins to mount an immune response against unhealthy cells ( 10 ). However, it must be noted that expression occurs under certain conditions also on healthy cells, especially by immune cells for immunoregulatory purposes ( 11 , 12 ). Third, the NKG2D ligand-NKG2D axis is widely recognized as anti-tumorigenic checkpoint.…”