Lectures 4-6 Flashcards
What are the mechanisms of endocytosis in professional APCs?
macropinocytosis, phagocytosis, receptor-mediated endocytosis, pinocytosis and autophagocytosis
Which methods of endocytosis are mediated by actin and which are mediated by clathrin?
actin: macropinocytosis and phagocytosis
clathrin: receptor-mediated endocytosis and pinocytosis
Which methods of endocytosis are triggered by a surface receptor?
phagocytosis and receptor-mediated endocytosis
What are the most important mechanisms of endocytosis for MHC II presentation?
macropinocytosis, phagocytosis and receptor-mediated endocytosis
What are examples of receptors which trigger phagocytosis?
PRRs, FcRs, CRs and apoptotic corpse receptors
What do PRRs recognise?
structures found only on the surface of microbes
What do apoptotic corpse receptors recognise?
“eat me” ligands
How are dying cells removed from the body?
release of “find me” signals by dying cells + shifting the balance of “eat me” and “don’t eat me” signals (efferocytosis)
What is an example of an “eat me” signal?
increased exposure of phosphatidyl serine on the extracellular side (molecule which is highly exposed on the cytosolic side)
this occurs when flippases are downregulated during apoptosis resulting in increased PS exposure to the extracellular environment
What is exposed PS recognised by?
phagocytes
What is defective efferocytosis associated with?
sustained inflammation (because damaged tissue is not cleared properly), autoimmunity and cancer
What does autophagy consist of?
the engulfment of cytosolic material by a membrane, forming an autophagosome -> accesses the endocytic route
Why is autophagy mostly used?
to allow digestion of the autophagocytosed material by the hydrolytic system of lysosomes
What are the steps in autophagy?
a double-membrane structure, the phagophore, grows around cytosolic material -> a double-membrane vesicle forms, the autophagosome -> endosomes and lysosomes fuse with the autophagosome to generate autolysosomes -> autolysosome content is degraded and degradation products transported to the cytosol for recycling
What material do B lymphocytes present?
only present material captured by the surface receptor
What happens once B lymphocytes have presented material captured by the surface receptor?
a T lymphocyte will recognise the material as foreign and become activated -> activation of the B lymphocyte to differentiate into an antibody producing cell
If it is good for B lymphocytes to present antigen, why don’t all B lymphocytes present as dendritic cells do (anything from the extracellular environment)?
it will become activated and the T lymphocyte will activate the B lymphocyte leading to the production of antibodies that are useless (very inefficient)
this is why B cells have restricted the antigen presenting capacity to material that they can recognise with their surface receptor
How are endocytosed proteins denatured in endosomal compartments?
acidification (H+-pump ATPases) and reduction of S-S bonds (GILT)
Why does MHC II associate with li?
to prevent binding of ER components
What is the role of the “molecular code” carried by li?
“tags” MHC II-li for transport to the endocytic route; the complexes would otherwise traffic directly to the PM (like MHC I molecules)
What is CLIP known as and why?
a promiscuous peptide because it fits in the peptide binding site of all MHC II allotypes
What are the steps which lead to substitution of antigenic peptides for CLIP?
a yet unknown protease cleaves the “zipper” region of li to generate lip10, releasing three aB dimers, each associated with one li-p10 fragment -> cathepsin S cleaves li-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
What is the role of HLA-DM?
subjects the MHC II-peptide complexes to editing so that only complexes carrying peptides that confer a minimum stability leave the endosomes
Why do we have dendritic cells?
because T lymphocytes cannot scan the whole body searching for pathogens
What are dendritic cells that have not seen pathogen dedicated to?
sample their environment by endocytosis and detect pathogens or tissue damage (immature DC)
What are dendritic cells that have seen pathogen dedicated to?
present antigens captured in their immune state and inform about type and location of pathogen (activated DC)
Why don’t dendritic cells present antigen after they have undergone maturation?
there is a decrease in the rate of synthesis of MHC class II molecules and a decrease in the ubiquitination of molecules that go to the surface (MARCH 1 is downregulated) -> provides a frozen snapshot of the material that was present when the dendritic cell was activated
What would happen if a dendritic cell first encounters the adjuvant of the vaccine and then there was activation and then it encounters the antigen of the vaccine?
this activated dendritic cell has downregulated MHC class II and downregulated endocytosis so now it would not be able to present the antigen
What happens if you link the antigen and the adjuvant together in a vaccine?
you ensure that every dendritic cell captures both at the same time so that you will get efficient presentation with every dendritic cell that encounters the vaccine
What happens during malaria as an example of having too much activation of dendritic cells?
the parasite multiplies and induces systemic inflammation which leads to all of the dendritic cells in the body becoming activated (therefore unable to inform the immune system because they will not present the antigen from the infection that happens after undergoing systematic activation)
Why don’t we want all cells to cross-present?
the T cells that you activate to kill the virally infected cells will kill not only the cells the cells that are infected with the virus, but every cell that is cross-presenting (needs to be restricted to certain cells)
