Adaptive Immunity Flashcards
Production of viral proteins
Viral proteins are made within the host cell, by the hosts own protein synthesis machinery
An effective immune system has to do what?
Devise a system to sample both vacuolar and cytoplasmic compartments
All proteins in a cell - both ____ and ____ are degraded into _____
Cellular; Foreign; Fragments (peptides)
Antigen presentation
Peptide fragments of proteins are “presented” to T cells on Class I or Class II MHC molecules
Concepts underlying class I MHC antigen presentation to T Cells
1) Proteins must be tagged for destruction
2) Protelysis must occur to generate peptides of the appropriate size
3) Peptides must be delivered to class I MHC molecules
4) Peptides must bind to class I MHC molecules
5) Peptides must be displayed to T cells in the context of class I MHC molecules
How are proteins tagged for proteolysis
Ubiquitin (small 8 kDa) added to protein destined for degradation - Ub on lysine residues
If a protein is destined for degradation, ubiquitin molecules are added to the ubiquitin to form a Ub chain
3 types of protease activity associated with proteasome
Chymotrypsin-like (The important one)
Trypsin-like
Capsase-like
IFN-γ
IFN-γ - protective cytokine usually associated with virus infection
Induces expression of 3 replacement of β proteasome subunits called LMPs, which increase the production of peptides suitable for antigen presentation (chymotrypsin activity)
Immunoproteasome
Proteasome once replacement subunits are encoded in the MHC
How many subunits in the proteasome
7
Actions of the proteasome
The ubiquitin must be removed before entry into the proteasome - done by isopeptidases
Unfoldases (associated with proteasome) stretch out the protein
Proteasome generates peptides of 4-20 amino acid residues
TAP (Peptide delivery)
Transporter associated with antigen processing - transports peptides into ER
TAP characteristics
Encoded in MHC
12 membrane spanning domain integral membrane proteins
One substrate: peptides
Peptides ending in L,I,V,M favored substrates
Size range:6-15 amino acid residues
What types of amino acids do degraded peptides end in
Hydrophobic (Leucine, Isoleucine, Valine, methionine)
Peptide generation and loading onto class I molecules (3 steps)
1) proteolysis of proteins - not totally random, but diverse (4-20 residues)
2) TAP transporter - selects for subset ending with L, I, V, M (6-15 residues)
3) Binding to class I MHC molecule - strict size restrictions and anchor residues (8-10 residues)
Class I MHC antigen processing and presentation (5 steps)
- Proteins tagged for destruction
- Proteolysis (peptides ending in L,I,V,M)
- Delivery of peptide (selction for L, I, V, M - enders)
- Binding of peptide (chaperone-mediated)
- Transport to the cell surface and presentation to T cells
Why don’t T cells recognize all cells as foreign
T cell receptors (TCR) recognize the combination of self MHC + peptide
How does a T cell know whether it is seeing self or foreign peptide?
During development, we generate a population of newborn T cells that have the capacity to recognize everything, including self peptide +MHC
Then we eliminate the T cells that recognize self peptide in complex with self-MHC
Alloreactivity
Some of the positively selected TCRs that bind weakly to self MHC + self peptide may bind strongly to non-self MHC and peptide
Thymic education (3 possibilities)
“Education” of T cells in the thymus
1) NO affinity - T Cell dies (death by neglect)
2) High affinity - T cell dies
3) Weak/moderate affinity - T cell lives to leave the thymus and populate the periphery
What causes rejection of transplanted tissue
Alloreactivity - reactivity of T cells to non-self (allogenic) MHC class I or class II molecules
Class I MHC chains (1 gene)
β2 Microglobulin, α1, α2, α3
Class II MHC chains (2 genes)
α1, α2, β1, β2
How do peptides contribute to MHC molecules
Considered a subunit of these MHC molecules - if no peptide bound, the MHC molecules fall apart
Class I molecules
Proteins must be tagged for destruction
Proteolysis must occur to generate peptides of the appropriate size
Peptides must be delivered to MHC molecules
Peptides must bind to MHC molecules (occurs in the ER)
Peptides must be displayed to CD8 T cells in the context of MHC molecules
Class II molecules
No tagging of proteins for destruction Proteolysis for antigen into peptides mediated by lysosomal proteases No topological barriers - delivery not an issue Loading of peptide occurs in endocytic compartment NOT in ER Peptides displayed to CD4 T cells in the context of MHC class II molecules
Why don’t Class II molecules face the problem of crossing the topological barrier of a lipid bilayer
Class II molecules present peptides that are derived from the outside of the cell i.e. endocytic pathway
How do we get class II molecules to the lysosome and how do we prevent peptides in the ER destined for class I molecules from binding to class II molecules
Invariant chain (Ii)
- Scaffold, stabilizer
- Barrier to peptides in ER
- Zip code to MHC class II compartment
Invariant chain
Forms a trimer with 3 class II molecules and 3 invariant chains
CLIP
Invariant chain binds in the groove of MHC class II molecule Cleavage results in a short peptide fragment (CLIP) bound to the class II molecule
HLA-DM
catalyzes the exchange between CLIP and the antigenic peptide
DM destabilizes peptide bound in the cleft
Class II antigen processing and presentation
1) No tagging of proteins for destruction
2) Proteolysis of antigen into peptides
3) Deliver to MHC
4) Loading of peptide
5) Peptides displayed to CD4 T cells
Can self peptides be presented by class II MHC molecules
Yes
How can extracellular peptides access class I MHC molecules (both CD4 and CD8 T Cells are critical to preventing viral infection)
Cross presentation - Occurs only in specialized antigen-presenting cells Can present engulfed materials to class I MHC (don't know why this happens)
Possibilities to explain Cross presentation (3)
1) ER fuses with endosome or phagosome
2) Antigen crosses phagosome membrane into cytoplasm
3) ER-derived phagosomes contain TAP and export machinery
What presents lipid moieties (antigens) to T-Cells
CD1 molecules - strikingly similar to class I and class II MHC molecules
Antigen presentation by CD1
CD1 assembles with β2m (like Class I)
NK-T Cells express classical T-Cell receptors that recognize lipid antigens held in the groove of CD1
Travels with invariant chain (like Class II) - expressed in antigen-presenting cells
Specialized antigen presenting cells
B cells
Dendritic cells
Macrophages
Peptide binding pocket
External domains of MHC I and MHC II molecules fold to form a peptide binding pocket
