W3L5 - NK Cells Flashcards
NK Cells Lineage
Common Lymphoid Progenitor in the bone marrow give rise to all lymphocytes including NK cells
NK cells are a large lymphocyte with granular cytoplasm
NK cells lack antigen specific receptors
- T cell receptors on T cells, B cell receptors on B cells
NK cells express various types of innate receptors (respond to cellular surface ligands)
Innate Lymphoid Cells (ILC)
Lymphocytes derived from common lymphocyte progenitor
- expression of transcription factor Id2 repress T and B cell development
- absence of T and B cell receptors and co-receptors
- express receptor for IL-7
Migrate to peripheral tissues (dermis, small intestine, lung)
Types of Innate Lymphoid Cells
ILC1
- stimulated by IL-12 & IL-18 from macrophages and DC
- produce INFɣ for defence against viruses and intracellular pathogens
- NK cells are a subset of ICL1, however ILC1 requires IL-7 for growth and development and NK require IL-15
ILC2
- stimulated by thymic stromal lymphopoietin (TSLP) and IL-33
- produce IL-4, IL-5 and IL-13
- protect against parasites
ILC3
- stimulated by IL-1β, IL-23
- produce IL-17 and IL-22
- defence against bacteria and fungi
NK Cells
Lymphoid cell (subtype of ILC1)
Part of the innate immune system
Kill infected, stressed or tumour cells
Release toxic granules (similar to CTL)
They are ready for action once they leave the bone marrow
Make up 5-15% of mononuclear cells in blood
Express germline DNA encoded receptors
In humans - identified by expressing CD16 (binds Fc region of IgG) and CD56 (adhesion molecule), as well as the absence of CD3
CD3-, CD56+
- cytotoxic NK cells (blood) = CD3-, CD56lo, CD16+
- immunomodulatory NK cells (LN) = CD3-, CD56hi, CD16-
NK Cells Elimination
NK cells eliminate virally infected, stressed cells and tumours
Can be done directly or indirectly
Direct contact - cytotoxicity by release of toxic granules (perforin and granzymes), apoptosis
Indirectly - produce IFN-ɣ and TNF
Indirect Protection
Activity of NK cells increased 20-100 fold by IFN-α, IFN-β or IL-12 produced by macrophages and DC
- response to many pathogens but especially virus infections
NK cells also produce large amounts of INFɣ and TNF
- activates macrophages, stimulates DC, induces CD4 to TH1
Serve to contain virus infection before cytotoxic T cells or neutralising antibodies of adaptive immune system starts
Direct Contact
NK cells eliminate both virally infected and cancer cells by direct contact
1. NK cells recognize reduced MHC class I molecules via activating and inhibitory receptors
2. Antibody Dependent Cell Mediated Cytotoxicity (ADCC)
- NK cells can attach to antibodies (via Fc receptor) on surface of cells (already bound to specific antigen receptor on target cell)
Direct cytotoxicity by release of perforin and granzymes
Apoptosis
Damaged, old or stressed cells need to be removed
Cells often express receptors (Fas and other death receptors) when stressed that once bound to the ligand initiate apoptosis
NK cells have on their surface:
- Fas ligand (CD95L) that binds to Fas (CD95) on target cell
- tumour necrosis factor related apoptosis inducing ligand (TRAIL) binding to death receptors (DR4 & DR5) on target cell
How do Activating and Inhibitory Receptors Work?
NK cells can distinguish healthy cells from infected and stressed cells by activating and inhibitory receptors on NK cell surface
Activating receptors
- stimulate protein kinases that phosphorylate down stream signalling substrates
Inhibitory receptors
- stimulate phosphatases that counter the kinases
- when inhibitory receptors engaged the signal stops the activating signal
Receptors on NK Cells
Balance of activating and inhibitory signals determines outcome of target cell
- activating receptors usually bind molecules that are expressed as a result of infection or malignancy (stress induced self)
- inhibitory receptors usually bind surface molecules that have high expressing and loss of these molecules indicate dysfunction (missing self)
Some of these receptors are very polymorphic and so different individuals will respond differently
Different NK cells express receptors to a larger or less degree than other NK cells within an individual
Types of NK Cell Receptors
Killer immunoglobulin-like receptors (KIR) - major receptors in humans - polymorphic - activating and inhibitory Killer lectin-like receptors (KLR) - Ly49 receptors in mice - polymorphic - activation and inhibitory NKG2 and CD94 - both lectin-like receptors - form heterodimer together - interact with HLA-E in humans and Qa1 in mice - HLA-E is not polymorphic but binds fragments of other HLA class 1 – detects reduced HLA class 1 (NKG2A, C, E and F)
Inhibitory and Activating Cytoplasmic Tails - Immunoreceptor Tyrosine-Based Inhibition Motif (ITIM)
When ligands bind (extracellular), the tyrosine in the ITIM becomes phosphorylated
Binds intracellular tyrosine phosphatases (SHP-1 and SHP-2)
Phosphatases (SHP-1 and SHP-2) become localised at cell membrane
These inhibit signalling by other receptors by removing phosphates from tyrosine residues of other signalling molecules
Long tails for KIR
Inhibitory and Activating Cytoplasmic Tails - Immunoreceptor Tyrosine-Based Activation Motif (ITAM)
Cytoplasmic tail associated with signalling protein called DAP12 (containing ITAM)
When ligation occurs ITAM becomes phosphorylated and activates tyrosine kinases (Syk or ZAP-70)
Further signalling lead to release of toxic granules
Killer Immunoglobulin-like Receptors (KIR)
Major receptors on NK cells in humans Members of immunoglobulin superfamily 17 genes or pseudogenes Encoded on chromosome 19 Highly polymorphic - number and type of KIR genes present - allelic variation within each KIR gene
KIR Structure and Nomenclature
Extracellular Ig domains (D) - 2D (binds HLA-C) - 3D (binds HLA-A & B) Cytoplasmic tail - long (L) - inhibitory - short (S) - activating For example: - KIR3DL1 = binds HLA-A & B + long inhibitory cytoplasmic tail (ITIMS)
