natural killer cell proliferation

Definition

Target type: biologicalprocess

The expansion of a natural killer cell population by cell division. [GOC:add, ISBN:0781735149]

Natural killer (NK) cell proliferation is a critical component of the innate immune response, enabling rapid elimination of infected or cancerous cells. This process involves a complex interplay of signaling pathways, transcription factors, and cellular interactions.

**1. Activation Signals:** NK cell activation is triggered by various signals, including:
* **Missing self:** NK cells recognize and kill cells lacking major histocompatibility complex (MHC) class I molecules, which are normally expressed on healthy cells. This "missing self" recognition is mediated by inhibitory receptors on NK cells, such as killer immunoglobulin-like receptors (KIRs) and leukocyte immunoglobulin-like receptors (LILRs).
* **Stress-induced ligands:** When cells become stressed or infected, they express stress-induced ligands, such as NKG2D ligands and ULBPs. These ligands are recognized by activating receptors on NK cells, triggering their cytotoxic activity.
* **Cytokines:** Cytokines such as interleukin-2 (IL-2), interleukin-12 (IL-12), and interleukin-15 (IL-15) can directly stimulate NK cell proliferation and enhance their cytotoxic potential.

**2. Signaling Pathways:** Upon activation, NK cells initiate a cascade of intracellular signaling pathways:
* **ITAM signaling:** Activating receptors on NK cells engage with intracellular signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs). These ITAMs recruit and activate tyrosine kinases like Syk and ZAP-70, triggering downstream signaling events.
* **MAPK pathway:** Activation of ITAMs leads to the activation of mitogen-activated protein kinases (MAPKs), such as ERK, JNK, and p38, which regulate cell proliferation, survival, and gene expression.
* **PI3K/AKT pathway:** This pathway plays a crucial role in regulating cell survival, growth, and metabolism. Activation of this pathway promotes NK cell proliferation by inhibiting apoptosis and promoting protein synthesis.

**3. Transcription Factor Activation:** Signaling pathways activate transcription factors, such as NF-κB, STATs, and AP-1, which regulate the expression of genes essential for NK cell proliferation. These transcription factors bind to specific DNA sequences in the promoter regions of target genes, leading to their upregulation.

**4. Cell Cycle Progression:** NK cells enter the cell cycle, undergoing a series of phases leading to DNA replication and cell division. Cyclin-dependent kinases (CDKs) and their regulatory proteins (cyclins) are key players in cell cycle progression, ensuring proper control and timing of cell division.

**5. Clonal Expansion:** Once activated, NK cells undergo rapid clonal expansion, resulting in an increased number of NK cells specific for the activating target. This allows for efficient elimination of infected or cancerous cells.

**6. Effector Functions:** NK cells exert their effector functions through:
* **Cytotoxicity:** NK cells release cytotoxic granules containing perforin and granzyme, which induce apoptosis in target cells.
* **Cytokine production:** NK cells secrete cytokines like IFN-γ, TNF-α, and GM-CSF, which modulate the immune response and enhance the activity of other immune cells.

**7. Regulation and Homeostasis:** NK cell proliferation and activity are tightly regulated by inhibitory signals, such as those mediated by KIRs and LILRs. These inhibitory signals prevent NK cells from attacking healthy cells and maintain immune homeostasis.'
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