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?
How are peptides generated for the exogenous pathway?
Peptides are generated from internalized antigens in endocytic vesicles.
- Particles are taken in within an endosomes.
- Endosomes are fused with lysosomes to become MHCl late lysosomes. –
- Late lysosomes becomes acidic, its contents are degraded
While the antigen is in a lysosome, what is occur with class 2?
MHC class 2 molecules are produced, and associated with invariant chain (Ii or CD74) and exported in vesicles from ER to the golgi
What does invariant chain do?
Invarient chain (li, cd74) guides transport of class II MHC molecules to endocytic vesicles?
- prevents peptides from binding to the groove too early in the ER
- also uses sorting signals in its cytoplasmic tail to direct MHC class II molecules
What happens to the inviariant chian?
The invariant chain (li) is initially degraded by proteoltic activity within endocytic comparetments to class II-assocaited invairant chain pepetide (CLIP) that remains in the groover.
HLA-DM exchanges CLIP for a peptide fragment
HLA-DO modulates the function of HLA-DM
What is the exogenous pathway of antigen processing and presentation overview?
What is CLIP?
What is HLA-DM
A protein whose gene are also found in the MHC gene region
- fundamental in switching peptide of MHC type II receptors
- similar in structure to the MHC type II receptor (alpha and beta chains) but has no peptide binding cleft
HLA-DM can replace a weakly bound peptide with one of grater affinity
- it stabilizes that MHC type II receptor for a greater life expectance once on the cel surface
What is cross-presentation?
Cross-presentation is the process by which some APCs can divert antigens collected from extracellular sources (exogenous pathway) to processing and presentation via MHC class I proteins (typically the realm of the endogenous pathway). This process is important for activation of naïve CD8 T cells to generate CTLs capable of detecting and lysing virally infected target cells. Dendritic cells, or a subset of this cell type, are thought to be the majorplayers in this process, although “licensing” by antigen-specific CD4 T cells may first be required in order for DCs to engage in cross-presentation.
What cell is the primary cross-presenting cell type?
Dendritic cells appear to be the primary cross-presenting cell type
How are nonprotein antigens recognized?
Mycolic acid derived from pathogens such as Mycobacterium tuberculosis is one classic example. These and other small lipid-containing antigens are presented by a small group of structurally similar proteins encoded outside the MHC locus: a group of nonclassical class I molecules, including the CD1 family of proteins and the MHC class I–related protein (MR1).
- presentation not via classic MHC molecules
- The CD1 and MHC class I - related MR1 family of nonclassical class I molecules can present lipids, lipid linked molecules, and for MR1 metabolites of vitamin B2
What is Bare Lymphocyte Syndrome?
Below normal levels of MHC
Defects in MHC gene transcription, MHC processing, Ag processing (TAP)
- if TAP cannot load Ag onto mHc molecules then it is not stabilized and will not move to surface
- TAP-deficiency: frequent bacterial infection, respoiraroty damage, and skin lesions due to unchecked NK cells
How does the immune system activate CD8 T cells to eliminate intracellular microbes unless a professional antigen-presenting cell happens to become infected?
The answer to this dilemma is a process called cross-presentation, blending the exogenous and endogenous pathways in a process that is still being fully resolved.
