Lecture 4 (Dustin) - MHC Presentation Flashcards
What does MHC stand for? What does it mean?
Major Histocompatibility Complex.
These are immunogenic alloantigen proteins on cell surface. Were discovered via research on organ transplants. Helps cells determine “self” vs “non-self” and induce an adaptive immune response
What are the subunits of MHC class I?
suggest you look at the lecture slide picture
Alpha 1, 2 and 3 (alpha 3 has a transmembrane domain)
Beta2microglobulin
(heterodimers)
What are the subunits of MHC class II?
Alpha 1 and 2, with a TM domain on alpha 2
Beta 1 and 2, with a TM domain on beta 2
Which cells contain MHC class I?
All nucleated cells (no red blood cells)
Which cells contain MHC class II?
Which cells recognize MHC class II?
Only professional antigen-presenting cells (APC’s) contain MHC class II
Th cells use their T cell receptor to recognize MHC class II in a complex with a presented antigen (“co-recognition”)
What does HLA stand for?
Human Lymphocyte Antigen
Which HLA's make up MHC class I? And MHC class II?
MHC Class I = HLA-A, HLA-B, HLA-C
MHC Class II = HLA-DP, HLA-DR, HLA-DQ
What are 4 things coded in the MHC III gene region (near the coding for MHC I and II)
MHC III region contains the things that make up C3 convertases (C4b, C4a, Factor B, C2)
What does it mean that the MHC gene coding regions are both polygenic and polymorphic?
Several different genes with similar functions -> individual has many different MHC molecules (polygeny)
Within an individual and across the population, a great diversity of MHC molecules is possible with both MHC class I and II due to both polymorphism and polygeny
What chromosome are the MHC encoding regions on? How are they inherited?
On chromosome 6 (“genetic hot spot”)
Co-dominantly inherited - both alleles of gene are co-expressed (from both mom and dad)
What regions of MHC Class I and II provide the most genetic diversity?
HLA-B provides the most diversity of MHC Class I
HLA-DRB provides the most diversity with MHC Class II
Can a single cell display just one type of MHC or many?
One cell can display a large array of MHCs.
All the somatic cells display the same HLA molecules. APC’s express both MHC class I and II HLA’s.
Apart from the “traditional” APC’s like dendritic cells and macrophages, what are two other types of cells that have MHC class II?
B cells and epithelial cells of the thymus (for T cell maturation)
How many amino acids are on an MHC class I peptide vs a MHC class II peptide?
Which one is “endogenous” and which one is “exogenous?”
MHC class I: 8-9 AA's, endogenous peptide MHC class II: 11-25 AA's, exogenous "non-self" peptide
Which MHC class is better at showing the cell has been infected by viruses or altered to a tumor cell?
MHC Class I: cytotoxic T cells notice the change of MHC class I due to DNA change (because it’s an endogenous peptide) and kill the cell
What problems is MHC class II good at showing to the immune system?
Foreign antigens like bacterial peptides, parasites. APC’s phagocytose these things, process them, and show their peptides with MHC class II to Th cells.
What are the two main pathways of receiving antigens?
- Cytosol-derived (endogenous antigens) - tumor or viral antigens, also intracellular bacteria
- endosome/lysozome-derived (exogenous antigens)
How are MHC I generated?
A self or viral protein in the cytosol is cut into peptide fragments by a proteosome. rER produces a new MHC I molecule, which binds the peptide and moves to the cell surface (the MHC is never expressed without a peptide complex). Peptides need access to the ER in order to be loaded onto class I molecules.
What is the TAP protein?
Transporter of Antigen Processing (TAP). It’s an ATP-dependent peptide transporter that brings peptides (prefers hydrophobic and >8 AA’s long) from the cytosol to the rER lumen and helps them bind in a complex with MHC I
What is the role of the beta2 microglobulin in the MHC I complex?
Stabilizes MHC I for correct peptide binding (probably more to it than this…)
What criteria do peptides have to have in order to fit into the MHC Class I cleft?
- Right size: 8-9 AA’s long
2. Two anchoring residues: phenol rings (from Tyr and Phe) and hydrophobic methyl groups (from Leu, Val, Ile)
Repeat from first lecture: what are the inhibiting and activating receptors to know for Natural Killer cells?
Inhibitory: NKG2A (the cell is A-OK!)
Activatory: NKG2D (D because the cell should die)
Remember NK cells kill ones without proper MHC class I identification
What is there to know about HLA-E, F, and G from the lecture?
These are “non-classical” HLA’s, they’re less polymorphic, limited repertoire of peptides presented to T cells.
NKG2A recognizes them
What are the 3 ways that phagocytes take up antigens? Which are the most effective?
- Lectin receptors (least effective)
- Fc gamma receptors (moderately effective)
- Complement receptors (most effective)
How do B cells take up antigens?
B cell receptors
Which protein binds the MHC class II groove so that no other peptides can yet bind until they’re ready?
What removes this peptide?
CLIP: Class II-associated invariant chain peptide. Prevents the MHC Class II from binding endogenous peptides.
HLA-DM removes CLIP
How does MHC Class II come into contact with exogenous peptides?
The rER and golgi produce lysosomes containing MHC II with CLIP occupying the binding site, and these fuse with endosomes of phagocytosed and degraded antigens. HLA-DM then both removes the CLIP peptide and coordinates the binding of exogenous peptides in CLIP’s spot.
What is the role of the invariant chain (Ii) in MHC Class II maturation?
The Ii chain starts out as a long chain that localizes and stabilizes the MHC II molecule inside a lysosome. It includes the CLIP portion that occupies the MHC Class II binding site. Inside the lysosome, most of the Ii protein breaks apart, except for the CLIP portion.
How do the antigen presentation goals of dendritic cells vs other phagocytes differ?
Dendritic cells carry the pathogen to the lymph node for naive T-cells to induce them to be activated/differentiated (priming)
B-cells and macrophages present the antigen to effector (not naive!) T-cells in order to get signals to facilitate their maturation
What type of T cells recognize endogenous antigens vs exogenous antigens?
Endogenous: Cytotoxic T cells
Exogenous: Helper T cells
What does “cross-presentation” refer to, with MHC presentation?
Exogenous antigens may be transferred to the ER and then be presented via the MHC I pathway, rather than the normal MHC II pathway
When might cross-presentation be useful?
Some viruses and tumors do not ever go to the lymph nodes, and so dendritic cells may take up their peptides in the extracellular space as exogenous antigens, but then these peptides should be presented as endogenous antigens to cause the more effective cytotoxic T cell response
What is “cross-dressing” in terms of MHC presentation?
Transfer of preformed peptide-MHC I complexes from the surface of infected cells to uninfected APCs, without the need of further antigen processing.
What other molecule that’s similar to MHC I can also present antigens? What kind of antigens?
CD1 is structurally similar to MHC I (also has 3 alpha subunits and beta 2 microglobulin), and can present (amphipathic) lipid, glycolipid, or lipopeptide antigens.
CD1 groove is larger, deeper, and more hydrophobic, and so it allows hydrophobic things in its groove and shows the hydrophilic parts on the outside to T cell receptors
How does the effect of superantigens differ from that of regular antigens?
What are 2 examples of superantigens?
Superantigens force an incorrect antigen presentation between TCR beta chain and MHC molecules. They cause non-specific T cell activation, polyclonal activation, with far too many cytokines being released -> systemic toxicity
Examples: SE (Staphyloccal enterotoxin), TSST-1 (toxic shock syndrome toxin-1 of staph aureus)
What kind of diseases are associated with HLA allele problems?
Mainly autoimmune diseases, like HLA-B27 of ankylosing spondylitis
Also seen in Grave’s disease, gluten-sensitivity, myasthenia gravis, psoriasis, type I diabetes, and rheumatoid arthritis
