Lecture 9: Mechanisms of Antigen Presentation on MHC Flashcards
Why do we have antigen presentation?
there are lots of intracellular parasites such as protozoans, bacteria and viruses which prefer living inside cells
How can T cells “peek” inside infected cells?
they don’t have to and instead examine the trash i.e. antigen presentation consists of displaying material that is part of the normal metabolism of cells which can provide information to the immune system about what is going on inside the cell
What happens when an infectious agent like a virus is present inside a cell?
causes a change in the material displayed by a cell e.g. abnormal proteins which can be detected by the immune system
What happens when a cell mutates into a form which could cause cancer?
those mutations can be displayed on the surface which can provide the basis for the ability of the immune system to fight cancer cells and destroy them
What is the role of MHC?
bind and display peptide antigens on the surface of the cell
enables antigen presentation
What are included in the antigenic determinants recognised by T cells?
residues from both the antigenic peptide and the MHC molecule
this is the structural basis for MHC restriction
What are the steps involved in the process of MHC class I antigen presentation?
infection e.g. virus -> synthesis of viral antigens -> proteasome degrades the antigen generating antigenic peptides -> peptides enter ER, where MHC I is synthesised -> peptides are inserted into the binding site of MHC I -> MHC I + peptide complex is transported along the secretory pathway to the plasma membrane
How are peptides able to enter the ER?
TAP translocates the peptides into the ER
What happens in the absence of pathogens?
MHC I molecules present self components
MHC I antigen presentation occurs constitutively (ongoing)
What does antigen presentation inform about?
the “health” of the cells; alterations in the proteome will be “sensed” as changes in the peptide repertoire displayed on the surface
What is the goal of MHC I presentation?
to display in real-time on the plasma membrane a sample of all the proteins synthesised by the cell
What is the MHC I presentation machinery is a combination of?
“multifunctional” proteins co-opted for an antigen presentation role, and “dedicated” proteins whose primary function is to assist in antigen presentation
What are “altered self” proteins also presented together with? Which obstacles must be overcome to deal with this?
presented together with “normal self” proteins
this requires to overcome obstacles imposed by the inherent physico- chemical properties of cellular structures
Where in the cell can pathogens live?
within endosomal compartments e.g. bacteria TB
Why can pathogens live within endosomal compartments? What is required in these situations?
because these compartments are separated from the proteasome MHC class II is required in these situations
What is the role of “professional” antigen presenting cells?
actively capture pathogens and present pathogen fragments to T lymphocytes
What are the steps involved in the process of MHC class II antigen presentation?
the APC endocytoses antigen -> endosomal proteases degrade the antigen -> the antigenic peptides are contained in endosomal compartments -> MHC II is synthesised in the ER -> MHC II binds the antigenic peptides -> MHC II peptide complexes are transported to the plasma membrane
What happens if you acidify a location where a protein is e.g. endosomal compartments?
the protein denatures which makes it much more accessible to proteolysis
How does acidification occur in endosomal compartments?
H+-pump ATPases lower the pH of endosomal compartments
How does reduction of S-S bonds occur in endosomal compartments?
GILT (g-interferon Inducible Lysosomal Thiol reductase) cleaves disulfide bonds
What are endosomal compartments?
highly proteolytic regions of the cell which are in charge of the turn-over of endogenous membrane proteins and endocytosed extracellular proteins
How do MHC I and MHC II differ?
MHC I peptide-binding site is formed by the heavy chain alone while MHC II peptide-binding site is formed by ɑ and β chains combined
What is the implication of MHC II being synthesised in the ER?
they have to traffic to the endosomal compartments where antigenic peptides are generated
What must MHC II molecules associate with due to the ER containing unfolded polypeptides and peptide ligands for MHC I? What does this prevent?
the invariant chain (li) to prevent binding of ER components
Which components associate with MHC II in the ER?
three MHC II ɑβ dimers which form an [ɑβli]3 nonamer
What is the role of a “zipper” region in the li?
promotes formation of a trimer
What is the role of the CLIP region of li?
occupies the peptide binding site of the ɑβ dimer
What is the CLIP region of li?
CLIP is a promiscuous peptide and fits in the peptide binding site of all MHC II allotypes
Why does li carry a “molecular code” in its cytoplasmic portion?
because this code “tags” MHC II-Ii for transport to the endocytic route; the complexes would otherwise traffic directly to the PM (like MHC I molecules)
What does the substitution of antigenic peptides for CLIP require?
li degradation and the chaperone HLA-2DM/H2-DM
What are the steps involved in the process of antigenic peptide substitution for CLIP?
a yet unknown protease cleaves the “zipper” region of Ii to generate Ii-p10, releasing three ab dimers -> cathepsin S cleaves Ii-p10 at the edge of the peptide binding site, generating ab-CLIP -> the chaperone HLA-DM interacts with ab-CLIP, inducing an “open” conformation in the ab dimer -> CLIP is substituted by an antigenic peptide
MHC I presents antigens degraded in…
the cytosol (mostly “endogenous”)
MHC II molecules present antigens degraded in…
the endosomes (both “endogenous” and “exogenous”)
What is MHC I expressed by?
(almost) all cells, because any cell can become infected with a virus, or become a tumour cell
What is MHC II expressed by?
specialised APCs which can capture antigens and “communicate” with T cells
What is the difference between MHC I and MHC II presentation?
in MHC I presentation the APC is normally infected with a virus, or is a tumour cell while in MHC II presentation the APC may not be infected itself, it just captured the antigen from the surrounding medium and is displaying it to T cells
What do cytotoxic CD8+ T lymphocytes interact with?
MHC I
What do helper CD4+ T lymphocytes interact with?
MHC II
How do T cells recognise antigens presented by MHC I and MHC II?
using different co-receptors
