Natural Born Killers: NK Cells And CD8+ T Lymphocytes Flashcards
What is the origin of natural killer cells and T cells?
Both arise from Mormon lymphoid progenitor cells
Both part of lymphocytes lineage
What is the role cytotoxic lymphocytes?
We need cytotoxic cells to be able to destroy cells infected with pathogen and tumour cells
Lymphocytes scanning a target cell surface to detect changes in protein production inside that target cell
What are natural killer cells and what is they’re function?
Cytotoxi INNATE immune cells
Kill virally infected targets
Kill tumour cells
Controlled by a balance of signals between activating/inhibitory receptors on their surface
Broad specificity for target cells
Why do we need more than one type of cytotoxic lymphocyte?
- To combat infection in the period before a T cell response develops
- To provide a alternative system when tumour or infected cells evade cytotoxic T cell responses
- To provide a additional mechanism for targeting infected target cells via antibody recognition
what is the correlation between NK cells and infection?
Low NK cell activity results in servere disseminating herpesvirus infections
What is the role of MHC 1?
MHC 1 proteins are found on th cell surface
They for a a structure that presents protein frangment at the cell surfaces or immune survallience
ALLOW A WAY FOR OTHER CELLS TO NOW WHATS HAPPENING INSIDE A CELL
Recognised by CD8+ cytotoxic T cells
How are intracellular proteins presented at the cell surface by MHC1?
Proteins are processed and presented on MHC1 proteins
- Proteins enter proteasome
- Proteasome breaks down protein into smaller peptide fragments
- Fragments enter the endoplasmic reticulum
- Fragments bind with MHC class 1 in the endoplasmic reticulum
- After binding the of complex migrates to the cell surface where it is presented
Describe the structure of MHC1
2 polypeptides not covalently bound
Peptide binding cleft at the top
- where short peptide fragment bind
— 2 alpha helixes with Beta pleated sheet between them
- amino acids form binding groves to relate pockets for where bound peptides can anchor
Beta2 micro globulin - forms lower structure
FOUND ON ALL NUCLEATED CELLS
where is the MHC gene complex located?
Chromosome 6
3 MHC class 1 Proteins
3 MHC class 2 proteins
Highly polymorphic - 100s of different genetic variants
What are Human leukocytes antigens (HLA)?
Human proteins
Why do we have HLA polymorphism?
Theory
High genetic variability within these gees may counteract the Pathogens ability to evade immune responses though their mutation
Where do MHC polymorphisms take place?
In the upper binding part of the MHC protein
Compare the variability to MHC 1 to MHC 2
MHC 1 has more variability
How is there variation in the biding groves of MHC 1?
Variation between different MHC alleles = variation in size, charge an location oof pockets = variations in peptides that can anchor within the pockets
What do T cell receptors recognise on NK + CD8 cells?
MC protein itself
Antigenic peptide presented by MHC protein
How does a T cell receptor bin to MHC 1?
Binds with a diagonal footprint that cuts across both alpha helices
Where does CD8 bind to MHC 1?
Binds to the lower part of MHC 1 (to the support domains)
whereas TCR binds to the alpha1+2 domain
What is the role of CD8?
acts as as a co-receptor for MHC-1, and is required for the T cell to make an effective response
How can pathogens prevent MHC 1 presentation?
Inhibit MHC1 transcription (adenovirus)
Block peptide transport into endoplasmic reticulum (HSV)
Retain MHC-1 in endoplasmic reticulum (adenovirus, HCMV)
Target MHC-1 for disposal from endoplasmic reticulum (HCMV)
Down regulate MHC-1 from cell surface
What is the function of killer ig-like receptors (KIR)?
Bind to MHC-1 and inhibit NK cells from releasing lyric granuels (NK cells survive)
Bind to the same face of MHC-1 as the TCR
A
What is meant but the term missing self?
When MHC-1 is not detected there is no inhibition of NK cell lysis so lyric granules will be released - NK cell dies
Are killer ig-like receptors (KIR) polymorphic?
Yes
And polymorphic individuals KIR genes vary in their presence between individuals
What are natural cytotoxicity receptors?
Receptors that provide activating signals to NK cells, but their range of ligands are not well characterised
Give examples of neutral cytotoxic receptors
NKp46
- binds to viral haemaglutinin
Nkp44
- binds a ligand that is expressed on tumour cells + unregulated by infection
Nkp30
- ligand is a stress induced protein
What is the balance between inhibitory and riveting signals needed for target cell death or survival?
MHC 1 binding - inhibitory - target cell survives
Activating receptor - activating - target cell lysis
More then one signal then another determines cell lysis or survival
Why do NK cells kill tumour cells?
Tumour cells can escape the adaptive immune system by down regulation of MHC 1 expression
Making them more susceptible to NK cells
How do Nk cell recognise antibody complexes on target cells?
By Antibody-dependent cell-mediated cytotoxicity (ADCC)
- Nk cells express receptor that recognises FCC portion of antibodies
- Receptor delivers a strong activating signal when it recognises antibodies bound to a cell surface
- Results in lysis of target cell
Describe the mechanism of lysis
- NK and T cells carry granules containing proteins
2 The cytotoxic granuels are released at the site of contact with the target cell
Must be directed to avoid damaging innocent bystander cells
What proteins are in the granules do cytotoxic T cells?
Perforin - aids in delivering contents of granules into the cytoplasm of target cells
Granzymes - serine proteases, which activates apoptosis once in the cytoplasm of the target cell
Granulysin - has anti microbial actions and can induce apoptosis
What is meant by a immunological synapse?
T cell receptor and CD8 cluster at the site of cell-cell contact
This polarises the T cell to release effector molecules at the point of contact
How can CD8 cells trigger apoptosis of target cells using Fas/FasL interaction?
Slower process than cytotoxic granules
- Fas LIGAND on T cells engages Fas on target cells to trigger apoptotic pathway
- FADD binds to Death domain on Fas
- Pro-caspase 8 then binds to death effector domain triggering a cascade
Fa/FasL triggered apoptosis is used to dispose of unwanted lymphocytes
What can occur as a result of loss of Fas?
Autoimmune lymphoproliferation syndrome (ALPS)
compare cytotoxic T cells and NK cells
T cells
- CD8 as a co-receptor for MHC-1
- Each express a unique an highly specific T cell receptor
- presence of appropriate MHC-1 ligand results in activation of Killing response
- absence of HC 1 ligand causes cell to move n after no recognition
- Response equites initial activation of naive T cells, followed by differentiation and proliferation
NK cells
- Do not use a co-receptor
- express multiple receptors including activating and inhibitory receptors
- Absence of appropriate MHC-1 ligand results in activation of killing response
- ready to act on encountering targets in periphery
REVISION TASK
MAKE A TABLE COMPARING NK AND CD8 CELLS
