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Combating Disease > Part 1: Antigen processing > Flashcards

Part 1: Antigen processing Flashcards

1
Q

What can CD4 & CD8 increase the sensitivity of ?

A

CD4 & CD8 can increase the sensitivity of T cells to peptide-antigen MHC complexes by ~100 fold

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2
Q

What 3 signals are required for activation of T cells by APC?

A
  1. Antigen-specific signal: peptide&MHC binding the TCR & coreceptor
  2. Costimulatory signal: T cell costimulatory CD28 binds B7 on APC
  3. Cytokines: IL-2 (key growth factor) & other differentiation cytokines and transcription factors
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3
Q

Explain Signal 2: Co-stimulation via CD28 & B7 molecules ?

A
  1. CD28
    - Found on T cells and needed for T cell autocrine secretion of IL-2
    - Constitutively expressed on T cell surface. Upregulated after
    activation
  2. CTLA4
    - Found on T cells and upregulated after T cells are activated.
    - Competes with CD8 for B7 to switch T cells off at the end of an immune response
  3. B7
    - Has two forms: B7.1 (CD80) and B7.2 (CD86)
    - Functional difference between B7.1 and B7.2 not known
    - Found on activated antigen
    presenting cells
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4
Q

What happens if there is no costimulation ?

A

T cells can neither divide ot survive

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5
Q

What does Co-stimulation provide ?

A

Co-stimulation provides an simultaneous signal to

permitting activation

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6
Q

Co-stimulation is restricted. What does this mean ?

A

Only Dendritic cells, macrophages & B cells express co-stimulatory molecules in the presence of infection/danger

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7
Q

Function of Phagolysosomes?

A
  • Vesicles fuse with lysosymes

- Acidification of vesicle activates proteasomes & hydrolases to degrade the contents into peptides

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8
Q

Where are MHC class II generated ?

A

In the ER

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9
Q

What does the Invariant chain?

A

Prevent peptides from binding MHC until it reaches the site of extracellular protein breakdown

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10
Q

What does HLA-DM catalyse?

A

Release of CLIP fragment of invariant chain

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11
Q

Invariant chain is cleaved to form ?

A

CLIP (class II associated invariant peptide) in endosomal compartment

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12
Q

The invariant chain is identical in all individuals and functions:?

A
  1. Prevent peptide binding
  2. Stabilise the conformation of the MHC class II (MIIC) until it binds peptide
  3. Deliver MHC class II into specialised endocytic vesicles where they bind peptides
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13
Q

What does MIIC proteases do?

A

Selectively attack Ii leaving CLIP on peptide binding grove

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14
Q

Peptide loading complex:

A

Chaperone proteins involved in the formation of the MHC I heterodimer

(1) Calreticulin & ERp57 stablisise until β2-microglobulin binds
(2) Tapasin facilitates binding to TAP which delivers peptides to MHC class I

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15
Q

Peptide loading complex aids the assembly & peptide loading of MHC I in ER

A
  • Degredation of proteins by the proteasome (cytosol) produces peptides
  • TAP delivers peptides to the ER
  • MHC class I is retained in the ER until peptide binds, completing the folding
  • The complex is then release from the ER for delivery to the membrane
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16
Q

Explain CD8+ ‘cytotoxic’ T cells (CTLs) ?

A
  • Generated in the thymus
  • Express T cell receptor & dimeric CD8 co-receptor
  • Recognise peptides presented by MHC Class I molecules (on all nucleated cells)
  • Important for immune defence against intracellular pathogens (viruses & bacteria) & tumour surveillance
17
Q

CD4+ versus CD8+ T cell Function ?

A

CD8+ T cell

  • Antigen specific killing of target (self) cell
  • Recognise antigen on MHC class I
  • Receive signals for activation
    (a) with CD4+ T cell help
    (b) without CD4+ T cell help
  • Produce cytokines
  • 2 major killing mechanisms:
    (a) Cytotoxic granule release
    (b) Fas-Fas-L killing

CD4+ T cell
- Differentiate into helper cell subsets

18
Q

Activation of killing by CTLs is highly destructive, requiring three signals:

A
  1. Priming by activated antigen presenting cells expressing
    antigen on MHC I
  2. Dendritic cells must have high intrinsic co-stimulation
  3. CD8+ T cell can then make its own IL-2 to drive proliferation
19
Q

Some CD8+ cytotoxic T cell responses require ?

A

CD4+ T cell help

20
Q

The problem -
Naive antigen-specific CD8+ T cells cannot directly eliminate transformed or infected cells without first to be activated by ‘professional’ APCs
What if the APC is not directly infected?

A

The solution -
- APCs need to acquire exogenous antigens from
the infectious agent and present them on MHC class I molecules - known as cross-presentation.
- Cross-presentation allows APCs to acquire antigens from non-APCs e.g. virally infected epithelial cells and present them on both MHC class I & MHC class II
- This provides the best stimulation for CTL activation

21
Q

What are Natural Killer T cells?

A

Lymphocytes with innate immune function - a first line of defence

22
Q

What are Natural Killer T cells important against ?

A

Particularly important against viral & bacterial infections and detection/limit development of cancer

23
Q

Death of target cells ?

A

Protective outcomes of CTLs and NK cells use different targeting mechanisms, but induce the same outcome

24
Q

NK cell receptors – licensed to kill by ?

A

‘Dysregulated self’

25
Q

What are the 3 structural families of germ-line receptors:

A
  1. KIRs – Killer cell Ig-like Receptors
  2. KLRs – Killer cell Lectin-like Receptors
  3. NRs – Natural cytotoxicity Receptors
26
Q

What can NK cells not do automatically ?

A

NK cells don’t automatically kill - they’re “licensed to kill” by interpreting signals from activating & inhibitory receptor interactions

27
Q

Normal cells present ligand for?

A

Activating (killing) receptor on NK cells AND ligand for inhibitory receptor (e.g. MHC class I)

28
Q

NK cell activation - summary?

A
  1. Strong inhibition
    - Healthy ‘normal’ cells
    expressing normal levels of MHC I
    - Protection from NK
    cell killing
  2. Reduced inhibition
    - Tumour / infection can
    downregulate MHC class I
    - NK cell will attack & eliminate these cells
  3. Strong activation
    - Tumour / infection can sometimes increase receptors recognised by NK cell activating receptors
    - Stronger activating signal
    than normal overrides inhibitory signal allowing
    NK cell attack
29
Q

Virally infected cells secrete?

A

Type I interferons also known as Anti-viral Interferons – IFNα & IFNβ

30
Q

What do both IFNα & IFNβ ?

A 
- Induce resistance to viral 
replication in all cells
- Increase MHC class I 
expression in all cells
- Increase NK cell killing
- Activate innate cells / recruit lymphocytes
31
Q

How is NK cell killing activity increased ?

A

NK cell killing activity is increased 100-fold by cytokines e.g. IL-12 from innate cells (macrophages, dendritic cells & sometime epithelial cells)

32
Q

What does IL-12 induce in NK cells ?

A

IL-12 induces NK cells to secrete Type II IFNγ secretion – crucial to for CD8+T cell activation & T helper differentiation

33
Q

Mechanisms of CTL & NK cell killing ?

A
  1. Cytotoxic granule dependent induced apoptosis
  2. Cytotoxic granule independent: Fas-Fas Ligand induced apoptosis
  • Both which are CD8 and NK cells
  • Both pathways result in the activation of caspase family proteases killing by apoptosis
34
Q

What do Cytotoxic granules contain ?

A
  1. Perforin – Pore forming to deliver granule contents to cytoplasm of target
  2. Granzymes – Serine protease function triggers caspase cascade → apoptosis
  3. Granulysin – Antimicrobial & assists in apoptosis
35
Q

What is Fas Ligand and what does it do ?

A
  • Fas Ligand – transmembrane protein expressed on CD8 CTLs & NK cells
  • Binds Fas on target cell leading to induction of apoptosis
36
Q

How does (Antibody-dependent cell-mediated cytotoxicity) work ?

A
  • NK cell express Fc receptor CD16 (FcγRIII)

- NK cells attack and destroy self cells coated with IgG antibody – opsonisation of target cells

Combating Disease (11 decks)

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