MHC II Flashcards
How do MHC-I peptides get generated?
Many come from defective ribosomal products (DriPs)
How are DriPs formed? Are they just human or viral?
- defectively folded proteins that often occur as a result of improperly spliced mRNAs or ribosomal frameshifts
- can be either viral or human proteins
How are misfolded proteins labeled for destruction?
misfolded proteins can be ubiquitylated
What is ubiquitylation?
- covalent addition of ubiquitin molecules to lyseine residues in misfolded proteins
- can form chains
- requires ATP and a series of enzymes
Where are ubiquitylated proteins targeted?
26S proteasome
What is the make-up of a 26S proteasome? What do the different subunits do?
20S core + 2(19S subunits)
- 19S “lid” binds ubiquitylated proteins, recycles ubiquitin and unfolds proteins that are not fully unfolded
- 20S core has proteases that chop up proteins into peptides
What is the immunoproteasome, where is it expressed, are there factors that upregulate its expression?
presented in pAPCs
the 20S core of the proteasome has some special subunits = the immunoproteasome
IFNg and TNFa upregulate the subunit expression in response to viral infection
What are the genes and proteins that make up the special subunits in the 20S portion the of the immunoproteasome? Where are these genes located?
- LMP2 -> Bi
- LMP7 -> B5i
- LMP10 -> B2i
genes are found in the MHC region of the genome
What are the differences between the peptides that the immunoproteasome creates vs normal proteasomes?
immunoproteasome increases the frequency of peptides that are the optimal size (8-10a.a) to bind to MHC-I which have C-term hydrophobic residues
What complex can IFNg generate and what does it replace and do?
generates the 11S PA28 proteasome-activator complex
replaces the 19S subunits
allows of faster peptide generation
What is the TAP transporter, what is it subunits (and where are these genes found), where does it get its energy, what does it transport into the RER?
TAP = transporter associated with Ag processing
subunits = TAP1 + TAP2 (genes in the MHC region)
energy = ATP
transports peptides that are 8-16 a.a in size that often have a hydrophobic C-term residue
What does ERAP do, and where is it located?
located = RER
function = trims peptides transported into the RER by TAP at the N-term to fit into MHC-I
Why doe ERAP have a low affinity for peptides < 8 a.a?
- doesn’t change the C-term
- doesn’t make too small
Describe MHC-I peptide loading.
- class-I alpha chain and B2M are synthesized into the RER lumen
- Calnexin and ERp57 help partially fold the alpha chain
- when B2M binds to the alpha chain, Calnexin is release and replaced with calreticulin and tapasin
- this complex associated with TAP = PLC
- when peptide is loaded, the MHC-I + peptide complex dissociates from the rest of the peptide loading complex
- MHC-I + peptide complexes exit the RER and travel to the cell surface
- peptides are presented to CD8+ T cells
What causes Bare lymphocyte syndrome type 1?
mutations in TAP1 or 2 genes causes patients to lack or express very little MHC-I on their cell surface
What are the consequences of Bare lymphocyte syndrome type 1?
- Number of CD8+ T cells are heavily reduced as MHC-I expression is critical for development of CD8+ T cells
- patients deal with many viral infections but have problems with respiratory bacterial infections
- repeated respiratory infections -> damage of the respiratory system
- develop necrotizing skin lesions due to excessive NK and gamma/delta T cell activation
How are exogenous proteins made into peptides for MHC-II loading?
- protein is internalized
- internalized Ag.s are degraded by peptidases in vesicles as pH of vesicles decrease
- endocytosed Ag.s/peptides end up in MHC-II late endosome for peptide loading (MIIC)
Describe MHC-II peptide loading.
- class II alpha and beta chains are synthesized into the RER
- MHC-II is complexed with an invariant chain (Ii) protein
- MHC-II/Ii complex moves to acidic endosomal vesicle
- Ii is cleaved due to the activation of acidic proteases (cathepsins)
- CLIP (class-II associated invariant chain peptide; a small peptide from Ii) still remains bound to the peptide binding groove to prevent peptides from binding to the peptide binding groove
- vesicles containing internalized Ag that have been broken down by proteases fuse with MHC-II/CLIP vesicles (MIIC late endosome)
- non-classical HLA-DM (present in the MIIC late endosome) binds the MHC-II/CLIP complex and promotes the release of CLIP and the binding of internalized peptide
- once peptide is loaded, MHC-ll/peptide complexes are trafficked to the surface to display Ag to CD4+ T cells
What are four functions of the invariant chain (Ii)?
- binds all MHC-II molecules
- prevents ER peptides from associating with MHC-II peptide binding groove
- helps fold MHC-II
- directs MHC-II out of the RER, through GA, towards acidic endosomal compartments
What causes Bare lymphocyte syndrome, type 2?
mutations in TFs that promote MHC-II promotion -> cells lacking MHC-II expression
What are the consequences of Bare lymphocyte syndrom, type 2?
- severly lack CD4+ T cells as MHC-II expression is critical for CD4+ T cell development
- SCID like phenotype:
- less Th cells to help: B cells respond to T-dep Ag, macrophages kill intracellular bacteria, Tc cells get activated
What is cross presentation? What is it important for?
in some pAPCs (e.g. DCs) exogenous Ag. can get into the MHC-I pathway, which is important for DCs to activate naive CD8+ T cells
