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11/19/23, 1:51 PM Full immuno notes to shareTopic 3 – antigen presentation to T lymphocytes by MHC
Class 1: CD8+
• All cells express MHC1 so all cells can demonstrate presence of viral pathogen within
it
Class 2: CD4+
• Only some cells use MHC2 (specialised thymus or gut cells)
EXAM Q: WHAT ARE 3 TYPES OF ANTIGEN RECEPTOR
A: T-CELLS, B-CELLS AND MHC MOLECULES
HOW CELLS ARE INFECTED
2 main intracellular compartments in cell separated by membranes
1) Cytosol
• Caused by Ag from the inside/intracellular environment
• Usually a virus that binds to cell, becomes internalised and hijacks cell to
generate more viral protein in cytosol
• Ag degraded and loaded onto MHC1
• Ag trapped and transmitted to outside via secretory system and Golgi
• Displayed on cell membrane
2) Vesicular system
• Ag is extracellular where bacteria/pathogen is in surrounding tissue fluid
• Cell takes in Ag via phagocytosis using endosomes and lysosomes/ membrane
bound vesicles
• Ag degraded
• Fragments displayed on cell membrane by MHC2
DELIVERING PEPTIDES TO CELL SURFACE USING MHC MOLECULES
Cytosolic compartment:
• Cytosolic pathogens like
virus or self proteins
• These are degraded to
small proteins within
cytosol
• Bind to MHC1
• Presented on CD8+ T-cells
(cytotoxic T-cells)
• Results in cell death
Vesicular compartment:
• Pathogens taken in in
membrane bound vesicle or endocytic vesicles
• Endocytic vesicles acidic and low pH
• Causes degradation of pathogens
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• Peptides bind to MHC2
• Ag presented to CD4+ (effector or helper t-cells)
• Either get signals activating macrophage to kill vesicular pathogens OR signals to
activate B-cell to become plasma cell and secrete immunoglobulins
• Ig will go on to eliminate other extracellular pathogens of the same type
Significance of using two different compartments to degrade Ag:
Separates two arms of the adaptive immune system
Viral proteins stimulate cytotoxic t-cell response
Extracellular pathogens stimulate t-helper cells and eventually the B-cell response
TAP COMPLEX (and cytosolic pathway - MHC1 molecules)
peptides that bind to MHC1 actively
transported from cytosol to ER via TAP
complex
Infected cell has both degraded viral
protein AND normal host cell protens that
were misfolded, old or not correctly
functional
So Peptides can be from pathogens
(viruses/intracellular bacteria) or degraded
self proteins.
These are transported to ER via Tap1 and
Tap2 which together make the TAP
complex
TAP complex:
• active transporter that binds ATP
• It forms a pore
• Hetrodimeric protein
• Polymorphic protein: can exist in a variety of forms and each form can transport a
different petide. Therefore there is some selectivity of peptides that can go via the
TAP complex
Go to ER as molecules in ER able to feed degraded peptides from cytosol to region in ER
where MHC1 is made
Peptides are generated in cytosol but proteolytic digestion occurs in proteasome
(organelle):
• 3D structure of 4 rings on top of each other, forming a pore
• Proteasome activator domains and catalytic core in centre
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1) Proteins labelled/flagged with ubiquitin to flag it for degredation in proteasome
2) Fed through catalytic chamber of proteasome
3) Proteolytically digested and degraded into small peptides
4) Peptides fed through TAP complex in ER
In times of infection the proteasome alters its beta units to become an immunoproteosome
• Produces peptides with hydrophobic C terminals
• Allows better recognition of the viral and self proteins
• Allows better binding in the groove of MHC1
Newly synthesised MHC1 are retained in ER until they bind a peptide:
The RER and cytosolic ribosomes are making new self proteins
If they are good and functional these stay in cytosol or are transported through ER to go on
and perfrom their particular function
Some non-functional or misfolded proteins (called DRiP’s – defective ribosomal proteins)
are designated for ubiquitination and destruction
• Both defective and viral proteins fed through proteosomal complex
• Degraded to peptide fragments
• Transported to TAP complex and into ER
MHC molecules are inserted into membrane
Its heavy chain is an alpha chain with 3 alpha domains
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When first made MHC alpha chains are unstable so they use chaperone proteins to help
overcome instability
For MHC1 chaperone used for the alpha chains in Calnexin
As MHC1 heacy chain made it is co-translationally insterted into the ER membrane and will
be associated with its chaperone
• Isnt in correct conformation and is a partially folded chain
• The beta macroglobulin (non-membrane part of MHC1) binds here but MHC1 still
unstable
• Chaperone changes to calreticulin
• MHC1 associates with Tapasin molecule allowing the partially folded macroglobulin
chain to bind close to the TAP complex.
After the peptide fragments go through the TAP complex they are further processed by
ERAAP
• = ER aminopeptidase associated with antigen presentation
• It is an aminopeptidase
• Therefore has function of trimming peptidase to correct size (8-10aa) before they go
past the MHC binding groove
• If they have correct peptide motifs they bind
• MHC is now able to adopt its final conformation
• MHC loses chaperone
• MHC becomes its recognisable shape and is released from the ER, through Golgi and
then cell surface
Therefore, MHC molecules do not go to cell surface unless they bind to the correct peptide
as they do not have their final conformation until they bind to this peptide.
Therefore MHC molecule rarely found on cell surface without a peptide bound to it
Many viruses produce immunoevasins that interefere
with Ag presentation by MCH1 and evade this process
Viruses subvert the immune system operational
mechanisms
e.g adenovirus produces E19 protein
• Inhibits binding of MHC to TAP by coming iin between
MHC and Tapasin
• This inhibits peptide engaging with MHC
• Without MHC bound to peptide the cell wont be
recognised by T-cells as it cannot present Ag to them
• Cell evades cytotoxic T cell response
Subverting immune response limits the virus’s detection by the immune system
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