Abstract
Natural killer (NK) cells are lymphocytes that play a major role in the elimination of virally-infected cells and tumor cells. NK cells recognize and target abnormal cells through activation of stimulatory receptors such as NKG2D. NKG2D ligands are self-proteins, which are absent or expressed at low levels on healthy cells but are induced upon cellular stress, transformation, or viral infection. The exact molecular mechanisms driving expression of these ligands remain poorly understood. Here we show that murine cytomegalovirus (MCMV) infection activates the phosphatidylinositol-3-kinase (PI3K) pathway and that this activation is required for the induction of the RAE-1 family of mouse NKG2D ligands. Among the multiple PI3K catalytic subunits, inhibition of the p110α catalytic subunit blocks this induction. Similarly, inhibition of p110α PI3K reduces cell surface expression of RAE-1 on transformed cells. Many viruses manipulate the PI3K pathway, and tumors frequently mutate the p110α oncogene. Thus, our findings suggest that dysregulation of the PI3K pathway is an important signal to induce expression of RAE-1, and this may represent a commonality among various types of cellular stresses that result in the induction of NKG2D ligands.
Highlights
Natural killer (NK) cells are specialized lymphocytes of the innate immune system that target both tumor cells and virallyinfected cells
NK cells recognize selfproteins, such as NKG2D ligands, that are poorly expressed on healthy cells but are upregulated on cells that are undergoing stress, such as infection and tumor development
We observed that mouse CMV (MCMV) activates the PI3K pathway and that this activation is required for NKG2D ligand expression
Summary
Natural killer (NK) cells are specialized lymphocytes of the innate immune system that target both tumor cells and virallyinfected cells. NKG2D ligands are upregulated in cells infected with viruses such as cytomegalovirus (CMV), measles, Influenza A, and respiratory syncytial virus [9,10]. To counteract this NK recognition, tumors and viruses have evolved ways to shed or block surface expression of NKG2D ligands [11,12]. Studies using mouse CMV (MCMV) with deletion mutations in genes encoding proteins that block ligand expression have shown that the ability of the virus to evade NKG2D recognition has a significant advantage on viral fitness in vivo [13,14,15]. Regulation of ligand expression under different conditions is critical to prevent targeting of healthy cells
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