MHC Flashcards
Where can infectious agents grow (2)
- Within the cytoplasms and/or nucleus of the cell.
- Within cell vesicles (endosomes and lysosomes) = ingested by phagocytosis results in the same location
If a pathogen enters via cytosolic pathogens, intravesicular pathogen and extracelllular pathogens/toxin, how is it:
1. Degraded in
2. Peptides bind to
3. Presented to
4. Effect on presenting cell
How do B cell and T cells differ in antigen recognition?
- B cells can recognize antigens via their surface Ig molecules
- T cells can only recognize antigen in association with a MHC molecule
What MHC type does cytotoxic T cells and helper T cells interact with and which cells can present these?
- Cytotoxic T cells: have TCR/CD8 receptors which interact with MHC type I receptors on all nucleated cell of the body
- T helper cells: have TCR/CD4 receptors which interact with MHC type II receptors on a subset of cells (B cells, macrophages, dendritic cells)
Why are T cell said to be MHC restricted?
Because T cells have a requirement to recognize antigens and the MHC molecule
What is the structure of MHC class 1 molecule?
- Class 1 molecules
- member of the Ig superfamily
- Structure
- 45 kDA glycoprotein α chain
* three external domains, (90 AA in length)
* transmembrane (25 AA)
* cytoplasmic anchor (30 AA)
- α chain passes through plasma membrane
- α1 and α2 domain: β-pleated sheet form the walls and two α form floor of the peptide-binding groove
- 12 kDa β2 microglobulin protein
- is similar to the α3 domain and also a part of the Ig superfamily
- non-covalently bound to MHC I α chain
What is the structure of the MHC Class II molecule?
- Class 2 molecule
- member of the Ig superfamily - Structure
- heterodimeric- 33 kDa α chain
- 28 kDa β chain
- both chain pass through the plasma membrane
- a peptide-binding cleft is formed by the pairing of the α1 and β1 domains
What are the peptide differences from MCH I and II
- MHC I
- peptide of intracapsular origin
- peptide 8-10 residues long
- deep pockets bind peptide side chains
- deep pockets bind peptide N and C termini - MHC 2
- peptides of extracullar origin
- peptide of 13-25 residues
- shallow pockets bind peptide side chains
- peptide termini free
- H-binds to peptide backbone
MHC locus encodes how many major classes of molecules?
- MHC locus encodes three major classes of molecules
- class 1
- class 2
- class 3
Describe the differences in MHC class 1/2
1. Peptide-binding domian
2. Nature of peptide-binding groove (open/close)
3. General size of bound peptide
4. Peptide motifs involved in binding to MHC molecule
5. nature of bound peptide
How are MHC genes inherited?
Allelic forms of MHC genes are inherited in linked groups called haplotypes
- each individual inherits one haplotype from each parent
Class I and II molecules exhibit ___________ in the __________ regino
polymorphism / peptide-binding region
How many different classes of Class 1 and 2 are there?
- Up to six for class 1
- up to 12 class for 2
Why is MHC very polymorphic?
Not due to gene rearrangement like B and T cells
Due to multiple alleles and great variation between alleles
What does it mean that MHC alleles are codominantly expressed?
- Both materanl and paternal MHC genes are expressed in offspring cells
- This gives the best chance for an organism to have some capavility of presenting all the possible antigen peptides it encounters
Why does MHC codominantly expression present a problem ?
Nonmatching MHC patterns will result in rejection of transplanted tissues
Where is MHC polymorphism found?
Differences tend to be clustered at amino acid locations within the groove sites
What can change MHC expression?
MHC expression can change with changing conditions
- Genetic regulatory componnets
- promotors that drive up transcription during times of infection
- Viral interference
- viruses like to shut down MHC class 1 expression because it targets the cells they’re in for destruction
- Cytokine-mediated signaling
- some cytokines expressed during infection/disease can drive up/down MHC expression
- Class 2 MHC alleles and antigen presentation
- different capability to present antigens may dictate overall strength of repsonse from individual to individual
What are the two likely explanations for variabvility in immune respnoisveness?
- Determinant Selection Model: This model states that each MHC molecule binds a unique array of antigenic peptides, and some peptides are more successful in eliciting an effective immune response than others
- Hole-in-the-Repertoire Model: T cells with TCRs that recognize certain foreign antigens closely resembling self-antigen may be eliminated during thymic development
Can T cell recognize whole antigens?
Who antigens cannot be recognized by t. cells- only processed antigen peptide gragments can be recognized
What type of processing does each T cell need?
- Class 1 presentation requires cytosolic or endogenous processing
- Class 2 presentation requires exogenous processing
How are endogenous antigens tagged and what protein prepares it for processing?
1.Peptides are generated by protease complexes called proteasomes
- tagged proteins are fed into proteasomes
ubiquitin proteins are used to “tag” intracellular porteins for constitiuve proteasomes degradation - a subtle variant known as an immunoproteasome cleaves ubiquinated proteins into fragments that pair better with MHC molecules
Give me the process of endogenous pathway starting at cytosol
- Peptides are transported from the cytosol to the rough endoplasmic reticyulum (RER)
- transporter associated with antigen processing (TAP) molecuels in the RER membrane move the fragments
- MHC class 1 molecuels lie in wait in the RER after their translation by ribosomes on its surface - chaperones aid peptide/MHC class 1 assembly
- clanexin, calreticulin, and tapasin help fold MHC class 1 and put it in close proximity to TAP
- ER aminopeptidase ERAP1 trims long peptides to a suitable size for MHC class 1 groover
What is the entire endogenous pathway of antigen processing and presentation?
