Regulation of ligands for the activating receptor NKG2D

Abstract

The outcome of an encounter between a cytotoxic cell and a potential target cell depends on the balance of signals from inhibitory and activating receptors. Natural Killer group 2D (NKG2D) has recently emerged as a major activating receptor on T lymphocytes and natural killer cells. In both humans and mice, multiple different genes encode ligands for NKG2D, and these ligands are non-classical major histocompatibility complex class I molecules. The NKG2D-ligand interaction triggers an activating signal in the cell expressing NKG2D and this promotes cytotoxic lysis of the cell expressing the ligand. Most normal tissues do not express ligands for NKG2D, but ligand expression has been documented in tumour and virus-infected cells, leading to lysis of these cells. Tight regulation of ligand expression is important. If there is inappropriate expression in normal tissues, this will favour autoimmune processes, whilst failure to up-regulate the ligands in pathological conditions would favour cancer development or dissemination of intracellular infection.

Figure 1

Multiple ligands for the human and mouse NKG2D receptor. Like major histocompatibility complex (MHC) class I molecules, MHC class I chain related proteins (MIC) A and MICB have α1, α2 and α3 extracellular domains and transmembrane domains. The remaining human and mouse ligands lack the α3 extracellular domain. Within the UL16 binding protein (ULBP) family, retinoic acid early transcript 1E (RAET1E) and RAET1G also have transmembrane domains, whilst ULBP1–3 are glycosylphosphatidylinositol (GPI)-linked proteins. Murine retinoic acid early 1 (Rae1) proteins are also GPI-linked to the membrane, whilst H60 and murine ULBP-like transcript 1 (MULT1) harbour transmembrane domains. The equilibrium dissociation constants (K_D) for the NKG2D–ligand interactions, as determined by surface plasmon resonance studies, are also presented (ND, not determined).

Figure 2

Phylogenetic tree illustrating the evolutionary relationships between the different human (dark grey) and mouse (light grey) NKG2D ligands, generated using Clustalw (http://www.ebi.ac.uk/clustalw/). Accession numbers: MHC class I chain related proteins (MIC) A, NP_000238; MICB, NP_005922; UL16 binding protein 1 (ULBP1), NP_079494; ULBP2, NP_079493; ULBP3, NP_078794; retinoic acid early transcript 1E (RAET1E), NP_631904; RAET1G, NP_001001788; retinoic acid early 1α (Rae1α), NP_033042; Rae1β, NP_033043; Rae1γ, NP_033044; Rae1δ, NP_064414; Rae1ε, NP_937836; H60, NP_034530; murine ULBP-like transcript 1 (MULT1), NP_084251.

Figure 3

Stringent regulation of NKG2D ligands is important. Failure to up-regulate the ligands in pathological situations, resulting in too little NKG2D signalling (left), can lead to the development of cancer, or the spread of infection. Conversely, inappropriate expression of the ligands, and hence too much NKG2D signalling in healthy cells (right), can lead to autoimmune disease.

Figure 4

A variety of stimuli that can regulate NKG2D ligands (NKG2DL) have been identified. However, little is known about the molecular mechanisms underlying the regulation of these ligands. There is evidence of transcriptional regulation, but the ligands may also be regulated at a level other than transcription. The solid arrows demonstrate the major regulatory pathways that have been identified. Indirect or less well-established pathways are shown as dotted arrows (ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3 related; Chk1, Checkpoint kinase 1; ConA, concanavalin A; IFN, interferon; IR, ionizing radiation; LPS, lipopolysaccharide; mTOR, mammalian target of rapamycin; NF, nuclear factor; PHA, phytohemagglutinin; PMA, phorbol 12-myristate 13-acetate).