The DNA Damage Response: A Common Pathway in the Regulation of NKG2D and DNAM-1 Ligand Expression in Normal, Infected, and Cancer Cells

Cristina Cerboni,Marco Cippitelli,Alessandra Zingoni,Alessandra Soriani,Cinzia Fionda,Margherita Doria,Angela Santoni

doi:10.3389/fimmu.2013.00508

Cristina Cerboni, Marco Cippitelli + Show 5 more

Open Access

https://doi.org/10.3389/fimmu.2013.00508

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Abstract

NKG2D and DNAM-1 are two activating receptors, present on the surface of NK cells and other cells of the immune system. Their ligands – MICA, MICB, ULBP1-6 for NKG2D, PVR/CD155 and Nectin-2/CD112 for DNAM-1 – can be constitutively expressed at low levels in some normal cells, but they are more often defined as “stress-induced,” since different stimuli can positively regulate their expression. In this review, we describe the molecular mechanisms involved in the up-regulation of NKG2D and DNAM-1 ligands under different physiological and pathological “stress” conditions, including mitosis, viral infections, and cancer. We will focus on the DNA damage response, as recent advances in the field have uncovered its important role as a common signaling pathway in the regulation of both NKG2D and DNAM-1 ligand expression in response to very diverse conditions and stimuli.

Highlights

The immune system is tasked with protecting the organism from pathogen attack, and with patrolling cells and tissues that have been dysregulated by non-microbial challenges, such as ultraviolet radiation, heat shock, oxidative stress, or tumor transformation
We describe the molecular mechanisms involved in the up-regulation of NKG2D and DNAM-1 ligands under different physiological and pathological “stress” conditions, including mitosis, viral infections, and cancer
Both oxidative stress and DNA damage response (DDR) were implicated in the induction of MICA and PVR on activated T cells [8, 27], suggesting that signaling via ATM/ATR kinases and DDR could represent a common pathway regulating the expression of NKG2D and DNAM-1 ligands on T lymphocytes (Figure 1)

Summary

INTRODUCTION

The immune system is tasked with protecting the organism from pathogen attack, and with patrolling cells and tissues that have been dysregulated by non-microbial challenges, such as ultraviolet radiation, heat shock, oxidative stress, or tumor transformation. In relation to activating ligands, studies performed in our own and other laboratories have shown that MIC, ULBP, and PVR molecules are induced on antigen-activated T cells [8, 27,28,29] (Table 1) Both oxidative stress (mainly mediated by a macrophage-dependent production of ROS) and DDR were implicated in the induction of MICA and PVR on activated T cells [8, 27], suggesting that signaling via ATM/ATR kinases and DDR could represent a common pathway regulating the expression of NKG2D and DNAM-1 ligands on T lymphocytes (Figure 1). Viruses have evolved a complex relationship with the DDR pathway being able to either inhibit or exploit DDR components in order to favor their own replication process, with some viruses using both strategies in a spatially

Cell model

Activating ligand

CONCLUSION