Immunology – Natural Killer (NK) cells. – Flashcards

Large, granular grainy appearance under microscope Part of innate immune system Make up 5-10% of lymphocytes in human peripheral blood Display cytotoxic activity against a wide range of tumor cells and against cells infected with viruses Do not have T or B cell receptors - must recognize abnormal cells in a different way.

Natural killer cells provide first line of defense against many viruses. As they can distinguish between infected and uninfected host cells they are able to target and kill infected cells. This allows them to eliminate the infection, or at least hold it in check until virus specific T cells and Ab can be produced. Natural killer cells also produce a variety of cytokines, such as IFN-γ and TNF-α, to regulate other cells of both the innate and adaptive immune system. IFN-γ and TNF-α stimulate maturation of dendritic cells which are key coordinators of both innate and adaptive immunity. INF-Y also activates macrophages and favors TH1 development over TH2.

Natural killer activity is stimulated by IFN-α, IFN-β and IL-12. IFN-α and IFN- β are released from virus-infected cells soon after infection → stimulate NK cells quickly leading to rise in NK-cell population. This allows containment of viral replication during period required for activation, proliferation and differentiation of CTL-P cells into functional CTLs.

The power of natural killer cells and other protective mechanisms of innate immunity is illustrated by RAG knockout mice, which lack T and B cells and are therefore totally lacking adaptive immunity. Natural killer cells and other mechanisms of innate immunity provide sufficient protection against infection if mice are raised in relatively clean conditions. The mice are able to reproduce and raise healthy offspring, however the offspring are more susceptible to infection and have a reduced lifespan.

1) CD122: IL-2 receptor 2) CD 49b: Integrin 3) FcγRIII: Receptor for the Fc region of IgG 4) Natural killer receptors: Set of unique activating and inhibiting receptors that are responsible for determining which targets natural killer cells will destroy.

1) Employ NK cell receptors to distinguish abnormalaties in target cell membrane protein profile (such as a reduction in class I MHC molecules and/or unusual profile surface Ags displayed by some tumor or virally infected cells.) 2) NK cells express FcγRIII (an Fc receptor) and can this bind to Ab-coated target cells (ex. tumor or virally infected cell) leading to antibody dependent cell mediated cytotoxicity.

Many virus-infected and tumor cells exhibit diminished MHC expression. NK cells can "identify" cells with reduced MHC expression and eliminate them.

NK cells employ two different categories of receptors: one that delivers inhibition signals to NK cells and another that delivers activation signals. NK cells distinguish healthy cells from infected or cancerous ones through a balance between activating signals and inhibitory signals Additional NK-activating signals can be delivered by cytokines. An activating receptor on a NK cell interacts with its ligand on an altered self cell (or if present, on a normal cell) inducing an activation signal that may result in killing. However, engagement of inhibitory NK-cell receptors by class I MHC molecules delivers an inhibition signal that counteracts the activation signal. Expression of class I molecules on normal cells prevents their destruction by natural killer cells. Because class I expression is often decreased on altered self cells, the killing signal predominates, leading to destruction.

1) Spares cells that express critical indicators of normal self (normal levels of expression of MHC class I molecules on membrane) 2) Kills cells that lack indicators of self (normal levels of Class I MHC absent from membrane)

Natural killer cells bear FasL on their surface and readily induce death in Fas-bearing target cells. The cytoplasm of natural killer cells has numerous granules containing perforin and granzymes. Unlike CTLs, which must be activated before granules appear, NK cells are constitutively cytotoxic and always have large granules in their cytoplasm. After NK adherence to a target cell, degranulation occurs, with the release of perforin and granzymes at the junction between interacting cells leading to apoptosis of the target cell.

Originally it was thought that only B and T lymphocytes could generate memory responses. Recent data indicates that some NK cells can also generate a memory response to antigen.

Natural killer cells expressing a receptor that binds to a viral protein could transfer memory of this antigen exposure to naive animals that had not been previously exposed/infected. Results of this experiment show that at least some natural killer cells possess the ability to become memory cells (ie. increase their longevity and improve their response time.

ADCC is mediated by natural killer cells, macrophages, neutrophils and eosinophils --> all of these cell types possess Fc receptor. When Ab is specifically bound to a target cell, cells bearing FcR can bind to Ab Fc region (and this to the target cell), subsequently causing lysis of target cell.