NK cells Flashcards
Describe NK cells.
Small cell- looks a bit like a lymphocyte.
Contains granules which contain killing machinery of cell. When these become activated by IL-2, they become large granular lymphocytes.
NK cells are very abundant cells in the blood, making up around 15% of leukocytes.
They express specific markers such as CD56 and NKRP46 that distinguish them from other leukocytes.
Use patients own NK cells to cure cancer tumour- could have toxic side effects.
Abundant in blood.
CD56 unique to NK cells.
NKR- activating receptor, unique.
Where are NK cell derived from?What are some similarities and differences to T cells?
NK cells are lymphoid cells derived from bone marrow progenitors.
In adult, all lymphoid cells are derived from bone marrow.
Similar to CD8+ T lymphocytes, NK cells can be activated with IL-2 to develop into potent killer cells.
NK T cells have T cell receptor, NK cells don’t.
Otherwise, have many features in common.
What are some key features of NK cell recognition?
Natural killer (NK) cells are part of the innate immune system.
They make up 5–15 % of peripheral blood leukocytes and a greater percent of resident leukocytes in certain tissues such as the liver.
Unlike B and T lymphocytes, NK cells do not express somatically rearranged receptors, but rather possess a variety of germline-encoded receptors.
NK cells are capable of recognising cells that are transformed or infected with pathogens and kill these cells via the release of cytotoxic granules or through death receptors.
Consequently, NK cells have been studied as potential tools for immunotherapy, especially in the treatment of leukemia.
Make a rapid response to pathogens/infection/damage.
Rearranged receptors- undergo gene rearrangement for maturation (immunoglobulins in B cells, T cell receptors in T cells).Transformed cell- cancer.
What do NK cells do and how are they controlled?
NK cells secrete cytokines such as IFN-gamma, which is pivotal in fighting infection and in shaping the developing immune response .
NK cell activity is controlled by signals derived from activating and inhibitory receptors.
In general, activating receptors recruit kinases through associated immunoreceptor tyrosine-based activating motif (ITAM)-containing proteins whereas the inhibitory receptors recruit phosphatases through the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) located in their long cytoplasmic tails.
Gamma- important for activating macrophages.
Signals- get both, but the more dominant one wins. Inhibitory is usually the more dominant one.
ITAM- Recruit kinases that can activate T and B cells through phosphorylation.
ITIMS- recruit phosphatatses, allows for inhibition and control through dephosphorylation.
What is the “missing-self hypothesis”?
Integration of all the inhibitory and activating signals determines whether the NK cells will kill or spare the target cells.
The inhibitory receptors mostly interact with major histocompatibility complex (MHC) class I ligands that normally present peptide antigens to CD8+ cytotoxic T cells.
Thus, cells evading recognition by CD8+ T cells through down-regulation of MHC class I proteins might become susceptible to NK cell-induced cytolysis.
MHC 1 expressed on every cell except RBCs- present peptides derived from antigens to cytotoxic T cells.
Switch off MHC 1, lose T cell detection, NK cells are secondary defence that can be activated.)
What does “ missing self” do?
Loss of MHC I removes the inhibitory signals provided by inhibitory receptors known as KIRs (killer inhibitory receptors) on NK cells, this allows NK cells to detect and eliminate infected or transformed cells that express one or more ligands for activating NK cell receptors.
NK cells can kill target cells. Pathogen can learn to downregulate MHC1- MHC normally inhibits NK cells, without MHC, NK cells are not inhibited.
What is needed for NK cells to kill virally infected cells?
What do NK cells need in order to activate?
Loss of inhibitory signals via inhibitory receptors is needed for NK cells to kill virally infected cells.
NK cell activation can’t occur without activating receptors that recognise ligands derived from host cells and pathogens. Actiavtign receptors are required for NK cells to deliver a cytotoxic signal.
What are the components of the NK cell killing machinery?
Granules containing perforin and granzymes.
Perforin- creates holes in plasma membrane of target cells.
Granzymes- serine proteases stored in NK cell granules and released on NK activation. Enter target cells via perforin-induced pores.
Activation of caspases induces target cell death.
FasL on NK surfaces induces apoptotic cell death via intercations with Fas death receptor on target cells.
What are the outcomes of the interferon response (IFN alpha and beta) from a virally infected cell?
Induce resistance to viral replication in all cells.
Increase expression of ligands for receptors on NK cells.
Activate NK cells to kill virally infected cells.
What are the two types of NK cell activating and inhibitory receptors?
Immunoglobulin like recpetors.
Lectin like receptors.
Both types of receptor recognise MHC class I- convergent evolution.
What are the different inhibitory receptors for MHCI on NK cells and what are their ligands?
CD94:NKG2A- complexes of HLA-E with peptides derived from the leader peptides of HLA-A, B, C.
KIR2DL1- HLA-C allotypes having lysine at position 80.
KIR2DL2/3- HLA-C allotypes having asparagine at position 80.
KIR3DL1- HLA-A and HLA-B allotypes having the Bw4 serological epitope determined by sequence motifs at positions 77-83.
KIR3DL2- complexes of HLA-A3 and HLA-A11 with a specific peptide from Epstein-Barr virus.
LILRB1- All HLA class 1.
What happens in target cells to allow HLA-E to bind to the CD94:NKG2a receptor on NK cells?
Leader peptides on polypeptides made on ribosomes in the cytosol allow the polypeptides to be translocated into the endoplasmic reticulum before they are folded into their proper conformation.
During this process the leader peptides are cleaved off.
The leader peptide cleaved from an HLA-A heavy chain is bound by HLA-E and brought to the cell surface to interact with the inhibitory receptor CD94:NKG2A receptor on NK cells.
How is CD94:NKG2a expression controlled by KIRs?
Immature NK cells first express CD94:NKG2a then express KIR.
If none of the KIRs expressed by the cell react with self MHCI, CD94:NKG2a is retained as the receptor for self MHCI.
If one of the expressed KIRs reacts with self MHCI, expression of CD94:NKG2a is turned off.
NK cells express diverse combinations of receptors, but all have one inhibitory receptor that recognises self MHCI.
How are the genes for many NK inhibitory and actibating receptors arranged?
Encoded by genes on human chromosome12 and 19 in loci called the NK complex (NKC) and Leukocyte receptor Complex (LRC) respectively. Receptors found in gene clusters.
These loci contain many other regulatory genes encoding regulatory receptors expressed on other leucocytes, eg. the siglec and CD66 families of inhibitory and activating receptors.
NKG2D is an important activating receptor expressed on NK cells, and the gene encoding NKG2D is also encoded here.
What are the ligands for NKG2D?
MHC like molecules- MIC-A and MIC-B.
RAET1 family members.
Expression of these is induced by cellular stress or transformation.
