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.
Highlights
The demands placed on the immune system are immense and highly complex
The expression of natural killer group 2 member D (NKG2D) ligands by monocytes and macrophages has been investigated by a number of groups, with results suggesting two primary functions. One of these functions was suggested by Hamerman et al, who showed that toll-like receptor (TLR) signaling through MyD88 in murine macrophages induced retinoic acid early inducible 1 (RAE-1) and that natural killer (NK) cells cocultured with these RAE-1-expressing macrophages internalized NKG2D from the surface both in vitro and in vivo [40]
A study by Ge et al showed that while ULBP1 and MHC class I polypeptide-related sequence A (MICA) were expressed at similar levels by peripheral blood mononuclear cell (PBMC) from children with Kawasaki disease and healthy controls, NKG2D expression by NK cells and CD8+ T cells was decreased in diseased patients, which correlated with increased cytokine production by monocytes [50]
Summary
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. 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 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.
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