Natural Killer Cells and Cytotoxic T Cells Flashcards
(28 cards)
Recap the two types of immunity
- Innate immunity = Non-specific, immediate response
- Active immunity = Highly specific, delayed response
Where do natural killer and T cells arise from?
- Both arise from a common lymphoid progenitor cell
- Both part of the lymphocyte lineage
What is the role of cytotoxic lymphocytes (aka T cells and NK cells)?
- Destroy cells infected with bacteria, viruses or parasites
- And tumour cells
- Requires a cell-surface mechanism to display what is going on in a cell (MHC)
Compare CTLs and NK cells?
What do MHC proteins do?
- MHC proteins will display what is going on inside the cells
- They are found at the cell surface and form a structure that holds antigenic peptides for surveillance by T cells
- HOWEVER = all intracellular proteins (mutated, infectious and healthy) can be presented at the cell surface by MHC class I
By what type of lymphocyte is MHC-Class I specifically recognised?
CD8+ Cytotoxic T cells
Recap (yr 1) How antigens from the cytosol are presented on MHC I?
- Viral proteins will be ubiquinated to the proteasome where it will be broken down into peptides
- These peptides will be transported to the ER via a transporter called TAP
- In the ER the MHC class I molecules are generated, here the peptides from the virus will be sampled if it forms a stable complex it will leave
- It will leave the cell via the golgi where it forms an exocytic vesicle which will fuse with the plasma membrane
Describe the MHC class I structure
- Alpha 3 domain and beta-2-microglobulin will form the base and provide support for the peptide binding groove
- The two alpha helices (alpha 1 and alpha 2) will form the groove where the peptides will bind
MHC class I proteins are central to anti-viral immune responses, so why dont we see many pathogens that have mutated to avoid antigen presentation?
- We have multiple MHC genes (HLA-A, B and C)
- There is a high genetic variabillity in these genes
How do MHC polymorphisms impact on MHC binding?
- Polymorphisms in the MHC are in the upper peptide binding part of MHC protein
- The peptide binding groove will create pockets where the bound peptide can ‘anchor’
- By substituting different amino acids, you will get different positive and negative charges as well as a varied size and shape of the binding pockets
- This will mean different peptides will bind to different MHCs due to the different alleles
- The peptide binding groove will create pockets where the bound peptide can ‘anchor’
What does the T cell receptor recognise?
- MHC protein itself
- Antigenic peptide presented by MHC protein
It is able to recognise this by binding with a diagonal footprint which cuts across both alpha helices and the peptide inbetween
How do we overcome the weak binding of MHC and T cell receptors?
- CD8 on T cells act as a co-receptor and strengthens the interaction between the T cell and MHC Class I
- CD8 will bind near the structural support region (a3 specifically)
- We do not see polymorphisms in this area but the upper peptide binding part as we could lose CD8 binding!!!
- Whereas TCR will bind to the a1-a2 heterodimer ligand and checks for antigenicity
How can pathogens adapt to stop being presented on MHC I?
- Microbes may subvert MHC upregulation
- Inhibit MHC-I transcription (adenovirus)
- Block TAP activity (HSV)
- Retain MHC-I in endoplasmic reticulum (adenovirus, HCMV)
- Target MHC-I for disposal from ER (HCMV)
- Downregulate MHC-I from cell surface (HIV)
What are natural killer cells?
- Large, granular lymphocytes (NOT B or T cells)
- They do not express T cell receptor (CD3) or B cell receptor
- They do express the cell surface marker CD56
What is the function of natural killer cellls?
- Cytokine secretion (esp. interferon gamma)
- Killing targets
Why are NK cells important in up-regulation of immunity?
- Medium to high cytolytic function was associated with reduced cancer risk; low cytolytic function was associated with increased cancer risk
- Low NK cell infection correlates with severe disseminating herpes virus infection
What are the two types of receptors found on natural killer cells?
-
Killer Ig-like receptors (KIR) = innate immune receptors which regulate the activity of NK cells
- Recognise MHC-I and inhibit NK cell from releasing lytic granules
- Leukocyte Ig-like receptors (LILR) = innate immune receptors which regulate function of NK cells
-
Natural Cytotoxicity Receptors (NCRS)
- Provide activating signals to NK cells
What are Killer Ig like receptors (KIR) and leucocyte Ig-like receptors encoded by?
- Encoded in a gene complex (leukocyte receptor complex or LRC) on chromosome 19
Describe the function of KIRs on NK cells
- When KIR recognise MHC-I they will inhibit NK cells from releasing lytic granules
- Some viruses will downregulate MHC as an evasion mechanism so loss of MHC-I is a common feature of tumour cells
- If a target cell does not express MHC-I then there is no KIR inhibition = lytic granule released to lyse the target
- Known as ‘missing self’
Describe NCRs
- These are natural cytoxicity receptors located on natural killer cells
- They will provide activating signals to NK cells
- however they are not well characterised (dont know everything about them)
- NCR 1 - binds viral haemagglutinin
- NCR2 – binds a ligand that is expressed on tumour cells and upregulated by viral infection
- however they are not well characterised (dont know everything about them)
What is natural killer cell activity controlled by?
- Control by the balance between inhibitory signals (when recognising MHC) and activating signals it is recieving from other receptors
How can antibodies activate NK cells?
- Natural killer cells express an Fc receptor (FcγRIII, CD16)
- FcγRIII will bind to IgG antibodies that have bound to antigens on an infected cell
- Cross-linking of Fc receptors will send an activating signal to the NK cell to kill the target cell by releasing its granule proteins
- This process is called ANTIBODY-DEPENDANT CELL MEDIATED CYTOTOXICITY (ADCC)
- This is a super activating signal of NK cells and will outweigh the inhibitory MHC signal on NK cells
How can NK cells kill tumour cells?
- Similar to pathogens, tumour cells will escape the adaptive immune system by downregulating the expression of MHC class I
- This will make them more susceptible to NK cells
Describe how cytotoxic T cells and natural killer cells will kill via cytotoxic granules?
- NK cells and T cells will carry granules filled with cytotoxic proteins
- Release cytotoxic granules at site of contact with target cell
- ! Must be directed in order to avoid damaging innocent bystander cells