L6 MHC antigen processing Flashcards
describe the antigen processing pathways
enogenous- synthesised in the cell e.g: virus antigens are presented
exogenous- antigens are taken from outside e.g: from bacteria and presented
antigen processing in mhc class 1?
- partly folded mhc class one chains bind to calnexin until B2m /?binds.
- mhc class 1 alpha: ( β2-microglobulin) B2m complex is released from calnexin, binds a complex of chaperone proteins (calreticulin and ERP5) binds to TAP via tapasin.
- cytosilic proteins and defective ribosomal proteins (DRPs) are degraded to peptides by the proteosome. TAP delivers peptides to the ER.
- A peptide binds the mhc class 1 and completes its folding. the mhc class 1 molecule is released from tap complex and exported to cell membrane.
TAP (Transporter Associated with Antigen Processing)
mhc class 1 alpha= mhc class 1’s alpha chain
what is the proteosome?
large multi-protein complex in cytosol. degrades misfolded proteins. proteosome inhibitors inhibit antigen presentation.
calreticulin?
blocks peptide binding sites, folds? it together to keep mhc class 1 stable.
proteosome structure?
first: alpha subunit, beta subunit, alpha subunit. converts proteins to be degraded to peptides. protosome is: 26S. 20S core: 4 stacks of 7 proteins. 7 diff alpha and 7 diff beta subunits. 3x beta subunits have active sites. these cleave amino acids. in an immune reaction some subunits get swapped by ifn-y. more efficient to generate more peptides. 19S regulator: ubiquitin - recognising proteins tagged with ubiquitin and unfolds so can enter catalytic core of proteosome. total of 6 active sites per proteosome.
proteosome substrates?
chymotrypsin-like: cleavage after hydrophobic residues.
trypsin-like: cleavage after basic residues.
post-acidic or caspase-like: cleavage after acid residues.
peptides after proteosome?
longer than those presented by mhc class 1. further trimmed by amino-peptidase in the cytosol and er. emino-peptideases: ERAAP (IN ER): trims 15aa to 8-10aa. induced by ifn-y. inhibition reduces cell surface expression of mhc class 1.
transport to er?
-transporter associated with antigen processing (TAP) pumps peptides to er.
-heterodimer of tap1 and tap2 proteins with 8 transmembrane domains. belong to ABC family (ATP-binding casette) of transporters.
- present in ER membranes.
TAP transports 8-15aa long peptides- have basic or hydrophobic cooh- termini
peptide loading complex?
-tap, calreticulin (general chaperone), Erp57: protein disulphide isomerase. assists disulphide bridge formation in peptide loading.
tapasin: encoded in mhc class 2 genome region. induced by ifn-y. reduced mhc class 1 expression in mutant cells. tapasin stabilises mhc class 1 binding to tap. forms a disulphide-linked dimer with Erp57. facilitates peptide binding _ edits? peptide binding for max affinity.
mhc class 2 invariant chain?
MHC Class II Protein Association with Invariant Chain
Invariant Chain: A specialized protein that assists MHC Class II molecule assembly Also called CD74
Key functions:
Prevents premature peptide binding in ER
Guides MHC Class II to correct cellular compartments
Structural Details
Type 2 Transmembrane Protein
Forms homotrimers (three identical protein units)
Not polymorphic (doesn’t vary genetically)
Encoded outside the MHC genome region
Molecular Mechanism
In Endoplasmic Reticulum (ER)
Binds to MHC Class II α and β dimers
Blocks peptide binding groove
Prevents premature peptide loading
Trafficking Mechanism
Targets MHC Class II molecules to lysosomal compartments
Lysosome contains degraded proteins
Allows proper peptide loading later in the process
Key Concepts
Prevents inappropriate peptide binding in ER
Guides MHC Class II to correct cellular processing sites
Ensures proper antigen presentation mechanism
antigen and mhc class 2 meet?
antigen and mhc class 2 meet in mIIc. antigen taken up from extracellular space into intracellular vesicles. in early endosome (neutral ph) endosomal proteins inactive. acidification of vesicles activates proteases to degrade antigen into peptide formation. vesicles containing peptides fuse with vesicles containing mhc class 2.
mIIc?
MIIC (MHC Class II Compartment) is specifically the compartment where MHC Class II molecules load peptides. It contains the class 2 chaperone HLA-DM. class 2 reside here 2-4h before going to cell surface. similar to endosomes and lysosomes (low ph +proteases present)
cathepsins S+L are proteolytic enzymes.
Invariant chain processing occurs here, where the chain is cleaved in mIIc, so the only peptide fragment is left in the groove. this fragment is CLIP (class 2 associated invariant chain peptide).
this invariant chain processing:
Prevents premature peptide binding
Guides MHC Class II trafficking
Prepares groove for actual antigen peptides
Occurs in MIIC compartment
HLA-DM?
Encoded in class 2 region of the genome. expression induced by ifn-y. detection of hla-dm: class 2 unable to bind peptides from internalised proteins. have clip proteins bound. localised to MIIC compartment where it releases CLIP from class 2, stabilises empty class 2 proteins and catalyses binding of peptides to class 2.
cross presentation?
Cross-Presentation Mechanism
Definition: Process where exogenous antigens are presented on MHC Class I molecules. Unique to dendritic cells. Bridges innate and adaptive immunity
Specific Scenario
Example: B virus infection
Normally, viral antigens would be presented on MHC Class II
Dendritic cells can present these viral antigens on MHC Class I
This allows CD8+ T cells to recognize and respond to the infection
Significance
Enables immune response to:
Extracellular pathogens
Viruses
Tumors
Allows CD8+ T cells to recognize antigens not from intracellular sources
Key Characteristics
Specialized function of dendritic cells
Breaks typical antigen presentation rules
Critical for comprehensive immune surveillance
