Innate immune recognition of double-stranded RNA triggers increased expression of NKG2D ligands after virus infection

Gloria Esteso,Susana Guerra,Mar Valés-Gómez,Hugh T Reyburn

doi:10.1074/jbc.m117.818393

Abstract

Self/non-self-discrimination by the innate immune system relies on germline-encoded, non-rearranging receptors expressed by innate immune cells recognizing conserved pathogen-associated molecular patterns. The natural killer group 2D (NKG2D) receptor is a potent immune-activating receptor that binds human genome-encoded ligands, whose expression is negligible in normal tissues, but increased in stress and disease conditions for reasons that are incompletely understood. Here it is not clear how the immune system reconciles receptor binding of self-proteins with self/non-self-discrimination to avoid autoreactivity. We now report that increased expression of NKG2D ligands after virus infection depends on interferon response factors activated by the detection of viral double-stranded RNA by pattern-recognition receptors (RIG-I/MDA-5) and that NKG2D ligand up-regulation can be blocked by the expression of viral dsRNA-binding proteins. Thus, innate immunity-mediated recognition of viral nucleic acids triggers the infected cell to release interferon for NK cell recruitment and to express NKG2D ligands to become more visible to the immune system. Finally, the observation that NKG2D-ligand induction is a consequence of signaling by pattern-recognition receptors that have been selected over evolutionary time to be highly pathogen-specific explains how the risks of autoreactivity in this system are minimized.

Highlights

Self/non-self-discrimination by the innate immune system relies on germline-encoded, non-rearranging receptors expressed by innate immune cells recognizing conserved pathogen-associated molecular patterns
We report that increased expression of natural killer group 2D (NKG2D) ligands after virus infection depends on interferon response factors activated by the detection of viral double-stranded RNA by pattern-recognition receptors (RIG-I/MDA-5) and that NKG2D ligand up-regulation can be blocked by the expression of viral dsRNA-binding proteins
2D; HDAC, histone deacetylase; ANOVA, analysis of variance; RLR, RIG-I-like receptors; interferon response factors (IRFs), interferon response factor; patternrecognition receptor (PRR), pattern-recognition receptor; VV, vaccinia virus; qPCR, quantitative PCR; PIV5, parainfluenzavirus type 5; BCDV, bovine viral diarrhea virus; PAMP, pathogen-associated molecular pattern; araC, arabinoside C; Western reserve strain (WR), Western reserve; baby hamster kidney (BHK), baby activating receptors are non-rearranging and essentially invariant, the ligands for these receptors are not pathogen-specific, but rather are encoded in the human genome [2] and, a system based on immune recognition of self, inevitably involves a risk of self-damage

Summary

Introduction

Self/non-self-discrimination by the innate immune system relies on germline-encoded, non-rearranging receptors expressed by innate immune cells recognizing conserved pathogen-associated molecular patterns. Histone deacetylase 3 (HDAC3) is known to be a repressor of ULBPs expression in epithelial cancer cells [9] and recently it was shown that expression of the murine cytomegalovirus protein M18, which blocks HDAC action, can lead to expression of ULBP1 [10] These authors proposed that in uninfected cells, constitutive HDAC activity normally suppresses NKG2DL expression, but that viral HDAC inhibition relieved this block, this passive model of regulation is likely simplistic and NKG2DL expression probably requires the recruitment of poshamster kidney; MICA/B, major histocompatibility complex class I chainrelated A and B; ULBP, UL16-binding protein; MAVS, mitochondrial antiviral signaling

Methods

Results

Conclusion