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2018 ; 9
(ä): 441
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NKG2D: A Master Regulator of Immune Cell Responsiveness
#MMPMID29568297
Wensveen FM
; Jelen?i? V
; Poli? B
Front Immunol
2018[]; 9
(ä): 441
PMID29568297
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NKG2D is an activating receptor that is mostly expressed on cells of the
cytotoxic arm of the immune system. Ligands of NKG2D are normally of low
abundance, but can be induced in virtually any cell in response to stressors,
such as infection and oncogenic transformation. Engagement of NKG2D stimulates
the production of cytokines and cytotoxic molecules and traditionally this
receptor is, therefore, viewed as a molecule that mediates direct responses
against cellular threats. However, accumulating evidence indicates that this
classical view is too narrow. During NK cell development, engagement of NKG2D has
a long-term impact on the expression of NK cell receptors and their
responsiveness to extracellular cues, suggesting a role in NK cell education.
Upon chronic NKG2D engagement, both NK and T cells show reduced responsiveness of
a number of activating receptors, demonstrating a role of NKG2D in induction of
peripheral tolerance. The image that emerges is that NKG2D can mediate both
inhibitory and activating signals, which depends on the intensity and duration of
ligand engagement. In this review, we provide an overview of the impact of NKG2D
stimulation during hematopoietic development and during acute and chronic
stimulation in the periphery on responsiveness of other receptors than NKG2D. We
propose that NKG2D interprets the context of the immunological environment
through detection of cellular cues and in response sets the appropriate
activation threshold for a large number of immune receptors. This perspective is
of particular importance for future therapies that aim to exploit NKG2D signaling
to fight tumors or infection.
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