Molecular mechanisms of natural killer cell activation in response to cellular stress

Abstract

Protection against cellular stress from various sources, such as nutritional, physical, pathogenic, or oncogenic, results in the induction of both intrinsic and extrinsic cellular protection mechanisms that collectively limit the damage these insults inflict on the host. The major extrinsic protection mechanism against cellular stress is the immune system. Indeed, it has been well described that cells that are stressed due to association with viral infection or early malignant transformation can be directly sensed by the immune system, particularly natural killer (NK) cells. Although the ability of NK cells to directly recognize and respond to stressed cells is well appreciated, the mechanisms and the breadth of cell-intrinsic responses that are intimately linked with their activation are only beginning to be uncovered. This review will provide a brief introduction to NK cells and the relevant receptors and ligands involved in direct responses to cellular stress. This will be followed by an in-depth discussion surrounding the various intrinsic responses to stress that can naturally engage NK cells, and how therapeutic agents may induce specific activation of NK cells and other innate immune cells by activating cellular responses to stress.

Immunosurveillance and therapy of multiple myeloma are CD226 dependent

“…We observed a robust increase in the number and the percentages of CD8 + T cells infiltrating the BM after 3 weeks of anti-CD137 mAb treatment, as compared to the cIg-treated mice (Figure 7, A-C, and Supplemental Figure 7). By contrast, the number of BM FOXP3 + Tregs remained stable after anti- Oncogene activation is a powerful inducer of cellular stress that not only activates apoptosis or senescence cellular programs (43), but also stimulates immune recognition through the upregulation of NKG2D and CD226 ligands (25,(44)(45)(46). It has recently been demonstrated in the EμMYC transgenic mouse model that replication stress induced by MYC overexpression is a strong inducer of CD155 expression (47).…”

Reactive Oxygen Species– and DNA Damage Response–Dependent NK Cell Activating Ligand Upregulation Occurs at Transcriptional Levels and Requires the Transcriptional Factor E2F1

“…The importance of DDR activation in the upregulation of activating NK receptor ligand expression is becoming increasingly clear (3,12,34,35). In regard to the NKG2D ligands, Gasser et al (2) demonstrated that NKG2D ligand upregulation is prevented by pharmacologic or genetic inhibition of ATM/ATR or Chk1 with no requirement for p53.…”

Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE

“…N atural killer cells belong to the cellular component of the innate immune systems and have cytotoxic and cytokineproducing capacities, which play a critical role in cancer immune surveillance (1,2). NK cell activation is regulated by various activating and inhibitory cell surface receptors, which detect nonself ligands or change in the expression of self-molecules on infected or transformed cells (2).…”

“…NK cell activation is regulated by various activating and inhibitory cell surface receptors, which detect nonself ligands or change in the expression of self-molecules on infected or transformed cells (2). NK cells need to be primed with cytokines such as IL-12, IL-15, and IL-18, and by crosstalk with accessory cells to achieve their effector potential (3).…”