lecture 3 Flashcards
what are TCR polypeptides encoded by?
rearranging genes
what are the variable regions encoded by?
V, D and J segments
how is diversity achieved with TCR?
-multiple V, D and J segments
-combinatorial diversity so randomly put together
-junctional diversity
how does rearrangement occur in T cells?
-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
what is TCR alpha chain similar to?
Ig light chain
what is TCR beta chain similar to?
Ig heavy chain
where do TCR recognise antigens?
in the groove of MHC molecules
why do we want MHC diversity?
so able to bind and present peptides to all different T cell receptors
how are MHC diverse?
-no gene rearrangement occurs
-co-dominantly expressed
what expresses class I MHC molecules?
all nucleated cells
what expresses class II MHC molecules?
particular cells- limited in cells that host and turn them on
eg. B cells, macrophages, dendritic cells- APCs
how many MHCs can a gene express?
-12 as can express up to six from both the maternal and paternal side
where do polymorphisms appear?
in clusters- occurs in same/similar place of MHC molecule
why is there such high levels of MHC polymorphism?
-allows binding of vast range of peptides that can be presented to T cells (popn can respond to lots of pathogens)
what are the downsides of high levels of MHC polymorphism?
-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)
how do peptides end up on surface of cells bound to MHC molecules?
- peptides derived from protein antigens synthesised inside a cell - presented by class I MHC molecules
- peptides derived from protein antigens taken up from outside of cell (exogenous)- presented by class II MHC molecules (dendritic cells, macrophages)
what are the ways in which cells encounter pathogens?
-by making the pathogens themselves (endogenous)
-from pathogen that has got into cell and hijacked protein synthesis machinery
why are the peptides processed?
-into small fragments suitable for binding to and presentation by MHC molecules
how are antigens presented by MHC class I molecules?
- 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
what is TAP?
-very specific component of a multi-protein
-peptide loading complex
what causes proteosomes to change their behaviour?
whatever is occurring outside the cell
what does TAP deliver?
-peptide that binds to the MHC class I molecule and completes its folding
-fully folded MHC molecule is released from TAP complex and exported
what happens once the peptide is in the ER?
-goes into binding groove and changes conformation of class I molecule
-can now leave ER to go to cell surface transported in a vesicle
what occurs with Mhc class II molecules?
-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
how are antigens processed and presented by MHC class II molecules?
- antigen endocytose into intracellular vesicles inside cell
- protein cleaved to peptides by acid proteases in vesicles
- vesicles fuse with vesicles containing MHC class II molecules
- peptides bind MHC class II molecules
- MHC II/peptide complex then transported inside vesicles to cell surface
what occurs with the invariant chain (light)?
- forms a complex with MHC class II molecule blocking the binding of peptides and misfolded proteins
- invariant chain is cleaved in an acidified endoscope leaving a short peptide fragment (CLIP) still bound to the MHC class II molecule
- endocytose antigens are degraded to peptides in endoscopes but the CLIP peptide blocks binding to peptides to MHC class II
- HLA-DM binds to MHC class II molecule, releasing CLIP and allowing other peptides to bind
- MHC then travels to cell surface
what occurs with MHC class I and class II of healthy uninfected cells?
molecules will bind and present peptides from self proteins
what’s the function of TAP and LMP in the class I pathway?
-transport peptides into ER for loading MHC
-LMP is part of proteasome so can subtly change the features of the proteasome
what is the function of HLA-DM in the class II pathway?
-edit the peptide that goes onto class II
-removes the clip
what is the function of cytotoxic CD8+ T cells?
-recognise cells that are infected by a virus and can kill them
