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Immunology and Infection > CD8 T cells > Flashcards

CD8 T cells Flashcards

1
Q

what do CD8 T cells transform into?

A

cytotoxic T cell killers

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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

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3
Q

what are the properties of CTL killing?

A
  1. rapid (kill quickly)
  2. highly specific
  3. can serially kill many targets
  4. at the site of infection they do not need a secondary co-stimulatory signal to kill
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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

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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
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6
Q

what are the different forms of cell death?

A
  • apoptosis

- necrosis

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7
Q

what is apoptosis?

A
  • natural cell death
  • physiological
  • cellular condensation
  • nuclear fragmentation (blebbing)
  • rapid phagocytosis
  • lack of inflammation
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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
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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
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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
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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
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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

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13
Q

what preformed cytotoxic granules do CTL killers release?

A

a. perforin
b. granzymes
c. granulysins

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14
Q

what is perforin?

A

delivers contents of granules to target cell cytosol

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15
Q

what are granzymes?

A

serine proteases that activate apoptosis when in the cytoplasm

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16
Q

what are granulysins?

A

anti-microbial activity

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17
Q

how quickly are cytotoxic granules released?

A

already synthesised so killing happens very quickly

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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
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19
Q

why is IL-2 important?

A

increases proliferation and survival

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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
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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
Q

what happens if you blocked the co-stimulatory pathway of 4-IBB?

A

the activated CD8 T cells die rapidly

26
Q

what does IL-2 drive?

A

proliferation

27
Q

what does IFN-y drive?

A
  • drives differentiation to the effector status (CTL)

- CD4 starts down the Th1 pathway which produces this IFN-y

28
Q

what features does a CD8 T cell have at an infected site?

A
  • 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
Q

how do CD8 T cells replenish the cytotoxic granule stores?

A
  • 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
Q

what is the role of Tbet?

A
  • Tbet induces granzyme B and preforin production
31
Q

what happens in the absence of Tbet?

A

there is a second pathway
- transcription factors EOMEs can substitute
also causes transcription of granzyme B and preforin

32
Q

what happens at the site of infection?

A
  • innate cells are at the site infected tissue, throw out IFN a and B
  • cells that are infected will be transformed
33
Q

how are infected cells transformed?

A

interferons can modify the proteasome to create an immunoproteasome

34
Q

what is the immunoproteasome?

A
  • 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
Q

what effect do innate immune cells have on entry?

A

innate cell are also changing the molecules at the site where cells enter to allow only activated T cells

36
Q

what signals do CD8 T cells need at infected tissue?

A
  • 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
Q

what are the roles of preforin and granzymes?

A
  • 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
Q

what are key features of the intrinsic apoptosis?

A
  • 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
Q

what is the role of Bcl-2 as the guardian of the mitochondria?

A
  • 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
Q

what are caspases?

A
  • cysteine proteases that cleave their substrates on the C terminal side of aspartate residues
  • inactive zynogens that require proteolytic modification to become activated
41
Q

what are the two classifications of caspases?

A
  1. initiators: activators

2. executioners: job is to kill

42
Q

how it the apoptosome formed?

A
  • 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
Q

how do caspases cause cell death?

A
  • initiator caspase 9 activates executioner caspases
  • targets inhibitor of caspase activate DNase (cleaved ICA)
  • CAD fragments DNA
  • get apoptosis and cell death
44
Q

what is blebbing?

A

intracellular contents starts getting a membrane around them

- reorganisation of cell membrane in apoptotic bodies

45
Q

where does phosphatidylserine relocates?

A

relocates from the intracellular surface to the extracellular membrane
- macrophages carrying receptors that recognise phosphatidylseirne enable engulfment

46
Q

why is blebbing important?

A

prevents the probability of autoimmunity and stops the viral DNA being taken up y other cells

47
Q

what is the extrinsic apoptosis pathway?

A
  • 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
Q

how does Fas trigger apoptosis via a death domain?

A
  • 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
Q

how is the extrinsic pathway used to get rid of all the cells once the infection is dealth with?

A
  • 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
Q

what happens when Fas-FasL is upregulated and the infection is over?

A
  • causes contraction and numbers plummet
51
Q

what does the immune system leave in place?

A
  • self-renewing stem like memory cells

- more powerful and responsive to what activated the CD8 cells the first time

Immunology and Infection (13 decks)

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