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3rd Year Biomed > Immunology (Liz lectures 2-4 - Antigen presentation) > Flashcards

Immunology (Liz lectures 2-4 - Antigen presentation) Flashcards

1
Q

Do T lymphocytes bind to to soluble antigens in the blood or to antigenic fragments presented on MHC molecules?

A

Only bind to antigens presented on MHC

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2
Q

Why is it important that cytotoxic T cells only respond to MHC presented antigens?

A

Production of cytotoxic reagents by cytotoxic T cells to soluble viral particles could be dangerous to normal cells

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3
Q

Why is it important that helper T cells only respond to MHC presented antigens?

A
  • If T helper cells reacted to soluble antigens it could cause uncontrolled cytokine production which can lead to autoimmunity
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4
Q

What is the structure of the proteasome?

A
  • Large cylindrical complex
  • 28 subunits arrange in 4 stacked rings of 7 subunits each
  • PA 28 binds to both ends of proteasome and is called proteasome activator
  • PA 28 changes the conformation of the alpha subunit allowing protein entry
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5
Q

What signals cause the production of PA28?

A

Only produced in response to IFN-gamma or TNF-alpha during inflammation
- replaces normal 19S cap

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6
Q

In response to these cytokines, the 3 enzymes beta1, beta2 and beta5 are replaced by what 3 different enzymes?

A

beta1i, beta2i and beta5i

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7
Q

What is the name for the proteasome after these changes have occured in response to inflammation?

A

The immunoproteasome

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8
Q

What tag is added to the viral proteins to target then to the immunoproteasome?

A

Ubiquitination

  • polyubiquitin chain added
  • Protein degraded into small antigenic fragments that bind better to MHC class I
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9
Q

How does the immunoproteasome sometimes contribute to autoimmunity?

A
  • Increased processing of self proteins through cell with high immunoproteasome levels
  • Increased self antigens expressed on MHC class I
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10
Q

What are the functions of the TAP1 and TAP2 transporters on the ER membrane?

A

Transport peptides from the cytosol into the ER lumen

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11
Q

What type of transporters are TAP1 and TAP2?

A

Part of the ATP-binding cassette (ABC) family

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12
Q

What happens in people have defects in TAP1 and TAP2?

A
  • Almost no MHC class I on cells

- Recurrent respiratory viral infections

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13
Q

Describe how MHC class I is assembled

A
  • Imcomplete MHC class I consists of 3 alpha subunits: 1,2 and 3
  • Imcomplete MHC class I bound to protein chaperone called calnexin
  • The beta-2 microglobulin binds to complex to complete MHC - calnexin dissociates
  • MHC then binds to chaperone proteins calreticulin and ERp57
  • These proteins cover antigen binding site of MHC
  • Binding of complex to TAP via tapasin
  • Calreticulin and ERp57 dissociate, allowing binding of degraded cytosolic proteins and defective ribosomal products (DRiPs)
  • MHC class I will antigen bound is transported to the cell membrane in an endosome
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14
Q

What are DRiPs?

A

Defective ribosomal products

  • include unstable proteins translated from mRNA
  • can be both self and pathogen derived
  • Recognised and tagged by ubiquitin for degradation by proteasome
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15
Q

What is ERAAP?

A

Endoplasmic reticulum aminopeptidase associated with antigen processing

  • trim amino-terminus of peptides if they are too long
  • Helps to fit peptides into MHC class I groove
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16
Q

ERAAP is regulated in response to what cytoking?

A

Interferon gamma (IFN-gamma)

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17
Q

Give some examples of how viral immunoevasins interfere with MHC processing

A

1) US6 and ICP47 prevent peptide movement through TAP
2) Adenovirus protein E19 competes with tapasin - inhibits peptide loading onto MHC
3) mk3 protein of mouse herpes virus - is a E3-ubiquitin ligase - ubiquitinates cytoplasmic tail of MHC I - targets it to the proteasome

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18
Q

Describe in basic the endosomic (class II) pathway of antigen processing

A
  • Antigen ingested by endocytosis or phagocytosis
  • Endosome fuses with lysosome
  • Antigens degraded and intergrated into MHC class II
  • MHC class II-peptide complex presented on cell membrane
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19
Q

What cells perfom class II antigen processing and how long does it take?

A

Only APCs e.g. macrophages, B cells and dendritic cells

Takes 1-3 hours

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20
Q

What does each class on TLR bind to?

A

1,2,4,5 and 6: bind to components on the surface of pathogens e.g LPS on bacteria

3,7,8 and 9: bind to rna or dna

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21
Q

Describe the process of PAMP recognition in TLR-1 and 2

A
  • TLR-1 and 2 have binding sites for lidip side chains of triacyl lipopeptides
  • Binding of each receptor to the same lipopeptide induces dimerisation
  • Dimerisation brings cytoplasmic TIR domains into close proximity
  • Toll-IL-1 domains dimerised starts signalling via MyD88 in most cases
22
Q

Describe how TLR signalling can activate the expression of pro-inflammatory cytokines

A
  • MyD88 recruits IRAK-1 and IRAK-4 to activate TRAF-6
  • TRAF-6 activates IKK-beta
  • IKK-beta phosphorylates IkB which is then degraded
  • NFkB is then released into nucleus, drivinf transcription of inflammatory cytokine genes such as TNF-alpha and IL-6
23
Q

Antigens internalised by endocytosis or phagocytosis are passed through multiple endosomes that decrease in what?

A

pH

  • early endosome pH 6-6.5
  • Through other endosomes
  • MIIC late endosome pH 4.5-4
  • Decreasing pH causes degradation into shorter peptides
24
Q

Antigenic peptides from endosomes are what length?

A

13-18 amino acids

25
How does MHC class II meet up with the peptides?
Migrate from the ER to the peptide containing compartment | - bind to peptide then transported to cell surface
26
Describe the process of peptide binding to MHC class II
1) Invariant chain forms a complec with MHC, blocking peptide binding 2) Invariant chain cleaved initially to leupeptin induced peptide (LIP10) 3) Then cleaved in acified endosome, leaving short peptide called CLIP bound to MHC 3) HLA-DM binds to MHC, releasing CLIP, allowing antigen to bind
27
What is the role of HLA-DO?
Can inhibit peptide-MHC II binding at the end of an immune response to end antigen presentation
28
What is the other role of HLA-DM?
- Checks for antigenic peptides weakly bound to MHC class II - Removes weakly bound peptides - Allows for peptides with higher affinity to bind - called PEPTIDE EDITING - important that the complex is stable as it much persist on the cell surface for many days
29
How is the MHC class II trafficked from the trans-golgi to the endosomal pathwat?
- The invariant chain contains sorting signals in its cytoplasmic tail
30
What are the general size of peptides bound to MHC class I?
8-10 AAs
31
What is the structure of the Class II MHC molecule?
4 subunits: - alpha 1&2 - beta 1&2 - 2 transmembrane domains
32
How many transmembrane domains does MHC class I have?
1 | - coming from the alpha-3 subunit
33
Describe the 3 signals that lead to niave T cell activation, survival and differentiation
Signal 1: - Binding of the peptide/MHC II complex on APC to the T cell receptor on the T cell - CD4 on T cell also binds to MHC class II - Causes ACTIVATION Signal 2: - Binding of B7.1 and B7.2 dimer on APC to CD28 on T cell (costimulatory signal) - Causes SURVIVAL Signal 3: - Production of cytokines from APC e.g IL-6 and IL-12 - Bind to T cell - Induced DIFFERENTIATION T cell then produces and responds to IL-2 leading to rapid cell division
34
What is the effect of: a) Only B7 binding (costimulation) b) Only antigen recognition
a) No effect on T cell (not activated) | b) Permanently inactivates T cell (anergy)
35
Describe the type of antigen uptake, MHC expression, location and effect of Dendritic cells, Macrophages and B cells
Dendritic cell: - Antigen uptake - macropinocytosis and phagocytosis - MHC expression - low on tissue-resident DCs, high on DCs in lymphoid tissue - Location - Throughout body - Effect - activation of niave T cells Macrophages: - Antigen uptake - Macropinocytosis and phagocytosis - MHC expression - Inducible by bacteria and cytokines - Location - Lymphoid and connective tissue, body cavities - Effect - activation of macrophages B cells: - Antigen uptake - Antigen-specific receptor (Ig) - MHC expression - Constitutive, increases on activation - Location - Lymphoid tissue, peripheral blood - Effect - delivery of help to B cells
36
What are the 5 main routes of antigen processing and presentation by DCs?
1) Receptor-mediated phagocytosis 2) Macropinocytosis 3) Viral infection 4) Cross-presentation after phagocytic or macropinocytic uptake 5) Transfer from incoming dendritic cell to resident dendritic cell
37
For each of these routes, explain the type of pathogen presented, the MHC molecule loaded and the type of niave T cell activation
1) Receptor-mediated phagocytosis - Extracellular bacteria - MHC class II - CD4 T cell 2) Macropinocytosis - Extracellular bacteria, soluble antigens, virus particles - MHC class II - CD4 cells The other 3: - Viruses - MHC class I - CD8 T cells
38
Why is cross presentation by DCs important?
Important way of activating CD8 cytotoxic T cells specific for viruses that do not infect APCs
39
How does cross presentation occur?
- Viral antigens endocytosed by phagocytosis or macropinocytosis - Antigen unfolded and reduced in size - Then transported across endosome membrane inot the cytosol by ATP-dependent transporter Sec61 - In the cytosol, the immunoproteasome cleaves the antigen as normal - Antigenic peptides enter the ER where theyre incorporated into MHC class I
40
What is macropinocytosis?
Regulated form of endocytosis that mediates the non-selective uptake of solute molecules, nutrients and antigens
41
What are Langerhans cells?
A form of immature DCs in the skin
42
What happens after Langerhans cells encounter a pathogen in the skin?
1) Ingest the pathogen by phagocytosis - These cells have no B7 yet 2) Migrate to local lymph nodes - Start to express B7 3) Some DCs now activate naive CD4 and CD8 T cells 4) Some pass antigens to DCs living in the lymph nodes
43
What are the 4 stages of conventional DC maturation?
1) Immature Dendritic cells enter particular tissues through chemokine receptors (e.g. CCR1) and bind to PAMPs of pathogens via receptors: - TLRs bind LPS and mannose - DC-SIGN binds mannose and fructose - Dectin-1 recognises fungal cell wall glucans 2) TLR signalling induces CCR7 which directs DC migration to the lymphoid tissue and augments expression of B7 3) Mature DCs in the lymphoid tissue express high levels of B7, MHC class I and II and adhesion molecules such as ICAM-1 4) Mature DCs activate T cells via the 3 signals
44
Describe the different roles of conventional vs plasmacytoid dendritic cells
Conventional: Activate naive T cells by presentation of antigens and co-stimulation Plasmacytoid: Produce large amounts of alpha and beta interferons in response to viral infection - Express intracellular TLR-7 and 9 to detect viruses
45
TLR-4 found in the phagosome recognises what? What does this help to control?
Recognises LPS (found on gram -ve bacteria) - Phagosomes containing LPS send peptide-bound MHC class II to cell surface - Phagosomes containing only self debris do not send MHC class II - Recognition of LPS bt TLR-4 helps to prevent autoimmunity
46
What are Polly Matzinger's rules of signalling for virgin and experienced T cells, virgin B cells and effector B and T cells?
Virgin T: Inactivate if you receive signal 1 but not 2. Signal must be from DC cells. Experienced T: Need both signal 1 & 2, but any APC will do. Virgin B: Need both signal 1 & 2 from activated T cells Effector B and T: can respond to only signal 1
47
How can DCs be utilised as a cancer immunotherapy?
- Cancer cells transfected with B7 gene - They can then provide both signal 1 and 2 to precursor cytotoxic T cells (CTL-P) - Causes differentiation into effector cytotoxic T cells that kill the cancer cell
48
Name another gene transfection that can cause tumour destruction
- Tumour cells transfected with GM-CSF gene - Secrete large amounts of GM-CSF cytokine - Causes activation of DCs - Increases cytotoxic T cell activation - Tumour destruction
49
How do DCs interact and respond to HIV?
- HIV binds to surface of mucosal DCs by binding of viral gp-120 ligand to DC-SIGN receptor - HIV internalised into early endosome - DCs migrate to lymph node - HIV translocated back to cell surface, then infects CD4 T cells
50
What are ISCOMS?
Immune stimulatory complexes | - Lipid micelles that enclode peptides in cytosol
51
How do ISCOMS deliver peptides to the class I processing pathway?
Fuse with membrane of APCs | - peptide transfered to the ER
52
What is a potential new application of ISCOMs?
- Possible means of delivering vaccine peptides to activate cytotoxic T cells - Immunisation agaisnt pathogenic viruses

3rd Year Biomed (44 decks)

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