Linking: Antigen processing Flashcards
Mhc 1 molecules -recap
Present peptides derived from within cell = endogenous antigens
Present to cd8+ cells —> cytotoxic
Mhc 2 molecules -recap
Presents peptides derived from outside the cell that have been endocytsoed - taken up = exogenous antigens from extracellular origin
Present to cd4+ T cells —> t helper cell
Describe antigen presentation
Not just one mhc + peptide = there are multiple = present to cd4+ and cd8+ T cells
Describe class 1 presentation pathway - gen
Requires cytosolic or endogenous processing
Presented to mhc before presentation on cell surface
Describe class 2 presentation pathway - gen
presentation requires exogenous processing
Presented to mhc before presentation on cell surface
What do mhc class 1 present
Endogenous pathogens
Describe endogenous pathogens
Mediate their own entry into cell = viruses, need to get into cell to replicate
Voluntarily want in to cell
By binding to receptors, endocytosis, membrane fusion
Name types of endogenous pathogens
Viruses
Intracellular bacteria or intracellular parasites
How are peptides generated - endogenous pathway
By protease complexes called proteasomes
How are peptides generated - endogenous pathway - tagged
Ub proteins used to tag intracellualr proteins for degradration
Tagged proteins fed into proteasomes
= chopped up into peptides
How are peptides generated - endogenous pathway - presentation
Self peptides are presented on mhc 1 as well - constant turnover of proteins and cells
Proteins in cells that are defective or for normal turn over
What serves as a signal fo recognition by proteasome
Polyub
= fed into proteasome and degraded
Tells proteasome to feed protein in and chop it up into fragments
What is very important for mhc class 1 pathway
Endoplasmic reticulum = for formation of peptide mhc class 1
Also important= peptide fragments generated at same time
Mhc class 1 - step 1
Partly folded mhc 1 alpha chain held in place by calnexin chaperone
Beta2microglobulin not bound yet
Mhc class 1 - step 2 chains
Mhc 1 alpha chain released from calnexin
Mhc 1 alpha and b2micro interact in presence of additional chaperons = calreticulin and erp57 = add b2micro and hold in place
Mhc class 1 - step 2 folding
Partly folded mhc class 1 binds to chaperon = tapasin to link it to tap
Mhc class 1 - step 2 cytosol
Meanwhile = protein are translated in cytosol and some are ubs = 30%= to be fed to proteasome - more than 70% of time proteins are normal
Mhc class 1 - step 3 - peptide
Polyub proteins get degraded by proteasome = produce peptide fragments
Brought into er by TAP = pump in peptides
Mhc class 1 - step 3 - peptide Binding
Eraap = trims peptides that are too long to bind mhc = only 8-10 aa can bind = only if fits it will bind
Peptide binding to mhc 1 will allow mhc to be properly folded, if no peptide = will remain partly folded
Mhc class 1 - step 4
Peptide binds to peptide binding groove mhc 1
Mhc 1 folding complete
Pmhc released from tap and chaperone protein
Then in vesicle = pmhc1 targeted for cell membrane
Describe exogenous pathogens
Pathogens taken up by immune cell = either by phagocytosis or endocytosis = form of engulfment = then processed and presented on mhc 2
Bcr binds antigen then endocytosis = creates vesicle sinking in = not like phago bc no pseudopodia
Name exogenous pathogens
Entry of these patheogns mediated by immune cells
Extracellualr bacteria, parasites, fungi
Exogenous pathway - how are peptides generated
Generated from internalized antigens in endocytic vesicles
Not all cells phagocytes but all can do endosomes
Exogenous pathway - describe endosomes
Particles taken in within endosomes (or phagosomes)
Endosomes fuse with lysosome = like phagolysosome, acidifies - bc proteolytic activity = chop up into peptide
Contents degraded
Exogenous pathway - simultaneously
Mhc clas 2 molecules are produced and exported from er in vesicles
Has o fuse = vesicles with peptide and with mhc = fuse = then presentation on cell surface
Describe mhc 2 molecules - formed where
In er
Describe mhc 2 molecules - binding
Invariant chain = li
Binds peptide groove of mhc 2
What does li do
Guides transport of class 2 mhc molecules to endocytic vesicle
Also uses sorting signals in its cytoplasmic tail to direct mhc class 2 molecule containing vesicles to peptide containing endocytic compartments = direct to vesicle with peptides
What does li prevent
Peptides from binding groove too early in teh er
Describe li and clip = whole process
Invariant chain binds groove of mhc class 2 molecule in er - mhc 2 ready so vesicle forms and will be transported
As transported = also acidifies and have proteolytic activity = invariant chain starts to degrade and only leaves
Clip = a small portion bound to peptide binding groove
How is li degraded
By proteolytic activity within endocytic compartments = to CLIP (CLass 2 associated Invariant chain Peptide)
Describe step 1 - mhc 2
Invariant chain in complex with mhc class 2 = binds peptide binding groove so peptides cannot bind
In er and in endocytic vesicle = other random proteins take up and invariant chain ensures they do not bind peptide binding groove
Describe step 2- mhc 2
Due to acidification = invariant chain cleaved by proteolytic activity = leaves clip bound to mhc 2 = in peptide binding groove
Describe step 3- mhc 2
Fusion with vesicle containing degraded peptides
Peptides still cannot bind mhc 2 bc clip is still blocking
Describe step 4 - mhc 2
Hla dm binds mhc 2 = binds to and stabilizes mhc class 2 molecules and releases clip = so peptide can bind
Peptide can bind peptide binding groove of mhc 2
Then PMHC2 targeted to surface
Describe hla dm = what is it/where
Very important role in vesicle - it is there teh whole time with mhc class 2
Mhc class 2 like molecules = structure similar but not peptide binding groove
Found predominantly in late endosomal compartment with invariant chain and mhc 2 molecule
