Natural killer cell

Natural killer cells (NKs) are lymphocytes that lack CD3 and express CD56. They are the main circulating lymphocyte that contributes to innate responses.

## Development

Early stages of development take place in the bone marrow.

Later stages appear to take place in lymphoid organs.

## Receptors

NKs express more than thirty types of inhibitory and activating receptors. Individual NK cells express only a selection of receptors.

NKs express two inhibitory receptors that recognize MHC class I.

**CD94:NKG2A -** Expressed first and has a broad MHC class I specificity.

**KIR -** Expressed later. NKs express varying numbers and combinations of KIRs.

NKs also express activating receptors that recognize stress-induced ligand, i.e. MIC-A and -B.

## NK cell education

During development, the NK must learn how to detect the loss of self-MHC class I on other cells.

## NK cell killing

Certain viral infections disrupt/downregulate MHC class I expression.

When an NK encounters a cell with **reduced MHC class I**, its signals from inhibitory receptors are weaker than what was experienced during its education. Activating receptors are engaged by binding to **stress-induced ligands** (e.g. MIC). When **activating signals overcome inhibitory signals**, the NK cells responds. In most cases, at least 2 different activating receptors must be engaged.

### Immune synapse

After an NK has made the decision to kill a target cell, it more firmly adheres to the target cell through stronger cell adhesion molecule interactions (LFA-1 : CR3). The interacting sets of receptors/ligands become concentrated at the surfaces of the two cells, forming an immune synapse.

The NK shoots out lytic granules containing cytotoxic compounds such as granzyme and perforin. Perforin, in particular, is a protease that disrupts the target cell plasma membrane. The target cell is induced to undergo **apoptosis**.

Intimate contact involving a sum of interactions is required to tightly regulate the killing activity of NKs.

### Antibody-dependent cell-mediated cytotoxicity (ADCC)

If a target cell is coated with IgG, the Fc portion can bind to the FcγRIIIA receptor on the NK. This FcR is the strongest activating receptor on NKs, and does not require a second type of activating receptor to trigger NK killing.

### Similarities and differences with CTLs

Similar

* Both form immune synapses with target cells
* Release cytotoxic compounds (e.g. granzyme, perforin) onto target cell surface to induce apoptosis

Different

* Recognition of target cells
	+ CTLs: TCR recognizes MHC I-peptide
	+ NKs: stress molecules (e.g. MIC-A and -B) along with absence of MHC class I
		- At least 2 different kinds of activating receptors must be engaged
		- No inhibitory receptors can be engaged

## Interaction with resident macrophages

NK-macrophage interactions can create a **positive feedback loop** to maintain/promote inflammation.

Mφs release chemokines (CXCL8 and IL-2) to recruit NKs. Upon cell-cell contact, Mφs produce 2 cytokines important for NK cell activation, proliferation and survival: IL-12 and IL-15. IL-12 promotes NK differentiation into an effector cell that secretes IFN-γ.

IFN-γ secreted by NKs can activate Mφs, increasing their capacity to secrete inflammatory cytokines and efficiency in the phagocytosis/destruction of (viral) pathogens.

## *In vitro*

If NKs > immature DCs, NKs appear to kill DCs.

If immature DCs > NKs, NKs secrete cytokines to induce DC maturation.