CD8 T cells Flashcards
1
Q
what do CD8 T cells transform into?
A
cytotoxic T cell killers
2
Q
what is the job of cytotoxic T cell killers?
A
kill cells that express peptide MHC complexes that are specific for the T cell receptor on CD9 T cells
3
Q
what are the properties of CTL killing?
A
- rapid (kill quickly)
- highly specific
- can serially kill many targets
- at the site of infection they do not need a secondary co-stimulatory signal to kill
4
Q
why do you want the CTL killers to be highly specific?
A
CTL cell singles out the infected cell as you dont want to kill healthy cells
5
Q
how can CTL serially kill many target cells?
A
- binds to an infected cell, kills it, detaches and the moves along to find the next
- need a lot of CTL cells
6
Q
what are the different forms of cell death?
A
- apoptosis
- necrosis
7
Q
what is apoptosis?
A
- natural cell death
- physiological
- cellular condensation
- nuclear fragmentation (blebbing)
- rapid phagocytosis
- lack of inflammation
8
Q
what is necrosis?
A
- pathological
- organelles swell
- membranes rupture
- leakage of cell contents
- marked inflammation
- release intracellular contents eg large amounts of DNA
9
Q
why is release of intracellular contents a problem during necrosis?
A
- triggers inflammation
- this can activate any APCs in the vicinity
- can be an autoimmunity problem
10
Q
how can autoimmunity be induced?
A
- pathogenic bystander activation
- infection sometimes trigger autoimmunity
- immune response itially to pathogen subsquently spreads to host tissue
11
Q
how can an infected cell lead to the destruction of your own cells?
A
- innate immune system kills by necrosis
- releases intracellular contents and infection particles
- picked up by DC and trafficked to a draining lymph node
- prime the T cells for specific infection
- at the same time you could prime T cells that are responsive to the intracellular
- starts to destroy your own cells
12
Q
what do T cells preferentially kill by?
A
- by apoptosis (programmed cell death)
- governed by a series of biochemical events and activation of proteases called capsases
13
Q
what preformed cytotoxic granules do CTL killers release?
A
a. perforin
b. granzymes
c. granulysins
14
Q
what is perforin?
A
delivers contents of granules to target cell cytosol
15
Q
what are granzymes?
A
serine proteases that activate apoptosis when in the cytoplasm
16
Q
what are granulysins?
A
anti-microbial activity
17
Q
how quickly are cytotoxic granules released?
A
already synthesised so killing happens very quickly
18
Q
what is the IL-2 IL-2R axis?
A
- APC delivers signal 1 and signal 2 to the naive T cell
- naive T cell produces IL-2
- upregulation of CD25, high affinity IL-2 receptor
- only when this is in place does the cell become responsive to IL-2 in the environment
- IL-2 binds to the surface and causes clonal expansion
- keeps sucking up IL-2
19
Q
why is IL-2 important?
A
increases proliferation and survival
20
Q
how are CD8 T cells controlled?
A
- receive signal 1 and 2 and release tiny amounts of IL-2
- upregulate the IL-2 high affinity receptor
- become responsive to environmental IL-2
21
Q
why can APCs activate CD4 and CD8 T cells?
A
- has peptides and can load them onto MHC I and II
22
Q
how does the APC activate CD4 T cells?
A
- activate CD4 T cell with 2 signals
- causes CD4 to produce CD40L to interact with CD40
- APC becomes hyper activated
- produces lots of MHC complexes
- CD4 produces IL-2
23
Q
how can an APC and CD4 activate CD8 T cells?
A
- CD8 receives the 2 signals
- upregulates CD25 and responsive to IL-2
- CD8 changes its surface molecules and upregulates a new costimulatory molecule thats specific for CD8 T cells
- this gives survival signals to the CD8 T cell thats activated
24
Q
what is the costimulatory molecule thats specific for CD8 T cells?
A
4-IBB that binds 4-IBBL on APC
25
what happens if you blocked the co-stimulatory pathway of 4-IBB?
the activated CD8 T cells die rapidly
26
what does IL-2 drive?
proliferation
27
what does IFN-y drive?
- drives differentiation to the effector status (CTL)
| - CD4 starts down the Th1 pathway which produces this IFN-y
28
what features does a CD8 T cell have at an infected site?
- has its preformed complexes of toxic granules
- contacts with the infected cell and releases them
- need to be replaced
- at the site of infection a transcriptional programme is activated
29
how do CD8 T cells replenish the cytotoxic granule stores?
- CD4 T cells continuously trigger CD8 T cells to replenish their cytotoxic granule stores
- IFNy produced by Th1 cell that binds IFNyR
- CD8 T cells have a IFNyR and this activates the transcription factor Tbet
30
what is the role of Tbet?
- Tbet induces granzyme B and preforin production
31
what happens in the absence of Tbet?
there is a second pathway
- transcription factors EOMEs can substitute
also causes transcription of granzyme B and preforin
32
what happens at the site of infection?
- innate cells are at the site infected tissue, throw out IFN a and B
- cells that are infected will be transformed
33
how are infected cells transformed?
interferons can modify the proteasome to create an immunoproteasome
34
what is the immunoproteasome?
- replacement of certain catalytic subunits of the constitutive proteasome
- peptides prodiced more receptive to binding MHC I
- proteins will be processed and released much faster (IFN-y modification)
- tap proteins are selecting the best peptides
- express peptide-MHC I that are the best fit for your CD8 T cell receptors
35
what effect do innate immune cells have on entry?
innate cell are also changing the molecules at the site where cells enter to allow only activated T cells
36
what signals do CD8 T cells need at infected tissue?
- stromal cells express MHC I but not co-stimulation
- once a CD8 T cell is activated its ability to pass on the cytotoxic molecules is based on triggering all the TcR
- only requires 1 signal at the site of infected tissue
37
what are the roles of preforin and granzymes?
- work together, form a multimeric complex
- stabilised by scaffolding molecules serglycin
- no receptor for preforin or granzyme
formation of immunological synapse is vital to prevent unwarranted death of healthy cells
- reorgnaisation of Golgi and microtbules
- form a tube between the two cells
38
what are key features of the intrinsic apoptosis?
- characterised by the movement of cytochrome c from the mitochondria
- mitochondria contains cytochrome c
- family anti-apoptotic molecules Bcl-2
- family of pro apoptotic molecules
39
what is the role of Bcl-2 as the guardian of the mitochondria?
- if Bax has increased round the mitochodnria
- Bcl-2 will bind Bax and stop it from polymerising
- granzyme B targets this
- granzyme B binds and activates Bid
- it binds the Bcl-2/Bax complex
- Bcl-2 releases Bax
- Bax self-polymersises
- produces pore and results in the release of cytochrome c
40
what are caspases?
- cysteine proteases that cleave their substrates on the C terminal side of aspartate residues
- inactive zynogens that require proteolytic modification to become activated
41
what are the two classifications of caspases?
1. initiators: activators
| 2. executioners: job is to kill
42
how it the apoptosome formed?
- forms a complex that enables activation of caspase 9 which initiates activation of executioner caspase 3
- complex of apoptotic protease activating factor 1 and cytochrom c
- binds pro-caspase 9
- another apoptosome binds on top
- starts the killing of the cell
43
how do caspases cause cell death?
- initiator caspase 9 activates executioner caspases
- targets inhibitor of caspase activate DNase (cleaved ICA)
- CAD fragments DNA
- get apoptosis and cell death
44
what is blebbing?
intracellular contents starts getting a membrane around them
| - reorganisation of cell membrane in apoptotic bodies
45
where does phosphatidylserine relocates?
relocates from the intracellular surface to the extracellular membrane
- macrophages carrying receptors that recognise phosphatidylseirne enable engulfment
46
why is blebbing important?
prevents the probability of autoimmunity and stops the viral DNA being taken up y other cells
47
what is the extrinsic apoptosis pathway?
- cytotoxic cells kills using on-cytotoxic granule-mediated mechanisms
- killing through the interaction of Fas on target cell and FasL on the CTL
- CD4 T cells can do this too
- most active in the thymus
- Fas triggers apoptosis via a death domain
48
how does Fas trigger apoptosis via a death domain?
- cells that express Fas
- downstream has the Fas Associated protein death domain
- forms a complex with pro-caspase 8 = Death Inducing Signal Complex and targets with executioner caspase 3
49
how is the extrinsic pathway used to get rid of all the cells once the infection is dealth with?
- turn the cells on each other
- Fas-FasL interactions are important at killing CTL once pathogenic threat is cleared
- upregulates Fas-FasL when infection is over
50
what happens when Fas-FasL is upregulated and the infection is over?
- causes contraction and numbers plummet
51
what does the immune system leave in place?
- self-renewing stem like memory cells
| - more powerful and responsive to what activated the CD8 cells the first time
