lecture 3

Question 1

what are TCR polypeptides encoded by?

Answer 1

rearranging genes

Question 2

what are the variable regions encoded by?

Answer 2

V, D and J segments

Question 3

how is diversity achieved with TCR?

Answer 3

-multiple V, D and J segments
-combinatorial diversity so randomly put together
-junctional diversity

Question 4

how does rearrangement occur in T cells?

Answer 4

-T cell randomly breaks its DNA between an alpha V region and an alpha J region
-then breaks between the D and J region bringing together a DJ complex
-this comes together with a V and encodes the beta chain

Question 5

what is TCR alpha chain similar to?

Answer 5

Ig light chain

Question 6

what is TCR beta chain similar to?

Answer 6

Ig heavy chain

Question 7

where do TCR recognise antigens?

Answer 7

in the groove of MHC molecules

Question 8

why do we want MHC diversity?

Answer 8

so able to bind and present peptides to all different T cell receptors

Question 9

how are MHC diverse?

Answer 9

-no gene rearrangement occurs
-co-dominantly expressed

Question 10

what expresses class I MHC molecules?

Answer 10

all nucleated cells

Question 11

what expresses class II MHC molecules?

Answer 11

particular cells- limited in cells that host and turn them on
eg. B cells, macrophages, dendritic cells- APCs

Question 12

how many MHCs can a gene express?

Answer 12

-12 as can express up to six from both the maternal and paternal side

Question 13

where do polymorphisms appear?

Answer 13

in clusters- occurs in same/similar place of MHC molecule

Question 14

why is there such high levels of MHC polymorphism?

Answer 14

-allows binding of vast range of peptides that can be presented to T cells (popn can respond to lots of pathogens)

Question 15

what are the downsides of high levels of MHC polymorphism?

Answer 15

-increases risk of immune mediated disease (autoimmune diseases)
-reduces pool of available donor organs for transplantation (body recognises self peptides from donor as pathogens and tries to remove-rejects the organ)

Question 16

how do peptides end up on surface of cells bound to MHC molecules?

Answer 16

1. peptides derived from protein antigens synthesised inside a cell - presented by class I MHC molecules
2. peptides derived from protein antigens taken up from outside of cell (exogenous)- presented by class II MHC molecules (dendritic cells, macrophages)

Question 16

what are the ways in which cells encounter pathogens?

Answer 16

-by making the pathogens themselves (endogenous)
-from pathogen that has got into cell and hijacked protein synthesis machinery

Question 17

why are the peptides processed?

Answer 17

-into small fragments suitable for binding to and presentation by MHC molecules

Question 18

how are antigens presented by MHC class I molecules?

Answer 18

• antigen (viral protein) synthesised in cytoplasm
• proteasome degrades/chops up the antigens in the cytoplasm
  -processed fragments move into endoplasmic reticulum by TAP transporter
  -peptide binds to MHC class I molecule
  -class I can move out ER and go to surface so is displaying the peptide from the antigen inside the cell

Question 19

what is TAP?

Answer 19

-very specific component of a multi-protein
-peptide loading complex

Question 20

what causes proteosomes to change their behaviour?

Answer 20

whatever is occurring outside the cell

Question 21

what does TAP deliver?

Answer 21

-peptide that binds to the MHC class I molecule and completes its folding
-fully folded MHC molecule is released from TAP complex and exported

Question 22

what happens once the peptide is in the ER?

Answer 22

-goes into binding groove and changes conformation of class I molecule
-can now leave ER to go to cell surface transported in a vesicle

Question 23

what occurs with Mhc class II molecules?

Answer 23

-loaded up with peptides from extracellular sources
-class II leaves ER and is targeted into the endocitic pathway where it meets the antigens from the extracellular pathway

Question 24

how are antigens processed and presented by MHC class II molecules?

Answer 24

1. antigen endocytose into intracellular vesicles inside cell
2. protein cleaved to peptides by acid proteases in vesicles
3. vesicles fuse with vesicles containing MHC class II molecules
4. peptides bind MHC class II molecules
5. MHC II/peptide complex then transported inside vesicles to cell surface

Question 25

what occurs with the invariant chain (light)?

Answer 25

1. forms a complex with MHC class II molecule blocking the binding of peptides and misfolded proteins
2. invariant chain is cleaved in an acidified endoscope leaving a short peptide fragment (CLIP) still bound to the MHC class II molecule
3. endocytose antigens are degraded to peptides in endoscopes but the CLIP peptide blocks binding to peptides to MHC class II
4. HLA-DM binds to MHC class II molecule, releasing CLIP and allowing other peptides to bind
5. MHC then travels to cell surface

Question 26

what occurs with MHC class I and class II of healthy uninfected cells?

Answer 26

molecules will bind and present peptides from self proteins

Question 26

what’s the function of TAP and LMP in the class I pathway?

Answer 26

-transport peptides into ER for loading MHC
-LMP is part of proteasome so can subtly change the features of the proteasome

Question 27

what is the function of HLA-DM in the class II pathway?

Answer 27

-edit the peptide that goes onto class II
-removes the clip

Question 28

what is the function of cytotoxic CD8+ T cells?

Answer 28

-recognise cells that are infected by a virus and can kill them