Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand–expressing tumor cells

Abstract

NKG2D is an activation receptor that allows natural killer (NK) cells to detect diseased host cells. The engagement of NKG2D with corresponding ligand results in surface modulation of the receptor and reduced function upon subsequent receptor engagement. However, it is not clear whether in addition to modulation the NKG2D receptor complex and/or its signaling capacity is preserved. We show here that the prolonged encounter with tumor cell-bound, but not soluble, ligand can completely uncouple the NKG2D receptor from the intracellular mobilization of calcium and the exertion of cell-mediated cytolysis. However, cytolytic effector function is intact since NKG2D ligand-exposed NK cells can be activated via the Ly49D receptor. While NKG2D-dependent cytotoxicity is impaired, prolonged ligand exposure results in constitutive interferon ␥ (IFN␥) production, suggesting sustained signal IntroductionNumerous activation receptors can trigger natural killer (NK) cell-mediated cytotoxic and/or cytokine responses. The NKG2D receptor is specific for endogenous ligands (ie, histocompatibility 60 (H60), retinoic acid early inducible gene-1 (RAE-1), and mouse UL16-binding proteinlike transcript 1 (MULT1) in mice), which are usually not expressed on normal resting cells but which are readily induced upon different forms of cellular distress (for a review see Raulet 1 ). Thus, the de novo expression of NKG2D ligands renders cells susceptible to NK cell-mediated lysis. On many tumor cell lines of distinct tissue origins, NKG2D ligands are constitutively expressed. The ectopic expression of NKG2D ligands induces the rejection of several transplantable tumor cell lines. 2,3 Despite NKG2D's prominent role in NK cell activation and T-cell costimulation, it is noteworthy that many established tumor cell lines constitutively express NKG2D ligands, suggesting that tumors can escape NKG2D recognition. Indeed, T and NK cells, which were infiltrating major histocompatibility class I chain-related protein A (MICA)-positive tumors had reduced NKG2D cell surface levels. 4,5 In vitro, soluble MICA or tumor cells expressing MICA induced the down-modulation and degradation of NKG2D expressed by CD8 ϩ T cells, which led to reduced effector functions. 4 In addition, NK cells derived from nonobese diabetic (NOD) mice (a strain of mice prone to autoimmune diabetes) displayed impaired NKG2D function. 6 NKG2D dysfunction and modulation were explained by an interaction of NKG2D with its ligands, which are aberrantly induced on NOD NK cells upon culture. 6 In general, reduced NKG2D function is thought to be the consequence of and directly related to the lower NKG2D cell surface levels. However, it has not been determined whether sustained NKG2D engagement leaves the NKG2D receptor complex and/or its signal transduction capacity intact. To this end we established a culture system in which NK cells are exposed to tumor cells expressing NKG2D ligand. We show that chronic engagement with tumor cell-bound NKG2D ligand can uncouple NKG2D recognition from the ex...

Requirements for control of B‐cell lymphoma by NK cells

“…4D). In mice expressing transgenic human NKG2D-L or harboring NKG2D-Lexpressing tumor cells, NKG2D down-regulation was also observed [40][41][42].…”

Natural killer cell immune escape in acute myeloid leukemia

“…100 Importantly, this strategy must be examined with scrutiny because sustained exposure of NKG2D ligands, either membrane-bound or in soluble form, to their receptor results in reduced NKG2D expression and impaired NK cell killing capacity. [102][103][104] Finally, several cytokines (for example, IFN-a, IL-15, TGF-b) were demonstrated to affect NKG2D ligand expression, but have not been tested on AML cells. 4,84 The proteasome inhibitor bortezomib and the histone deacetylase inhibitor depsipeptide were also shown to improve NK-cellmediated killing of AML cells through the death-receptor pathway TNF-related apoptosis-inducing ligand (TRAIL).…”

Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo

“…20,21 Thus, it is possible that sustained engagement of NKG2D by iMICA protein might decrease the expression of NKG2D on the surface of NK cells. However, we found that the expression of NKG2D in NK cells activated for 1 week did not decrease when compared with freshly isolated NK cells (Figure 1e).…”