Antigen Presentation. Flashcards
antigen presenting cells
macrophages, dendritic cells, and B cells that process and present foreign pathogen antigens for the purpose of activating T cells and adaptive immune defenses
MHC molecules display…
peptides derived from protein antigens
T cells recognize peptide antigens displayed by…
MHC molecules on APCs
Major Histocompatibility Complex (MHC)
The major histocompatibility complex (MHC) is a group of genes that encode proteins on the cell surface that have an important role in immune response. Their main role is in antigen presentation where MHC molecules display peptide fragments for recognition by appropriate T-cells.
describe the process of how microbial antigens are transported to lymphoid organs where recognition by T cells occurs
- dendritic cells residing in tissues capture microbes and antigens
- cell-free antigens are drained via lymphatic vessels
- antigens enter blood stream
- lymph node collects antigen from tissue
- blood born antigens are captured by antigen presenting cells in the spleen
the majority of dendritic cells in tissues and lymphoid organs are…
classical dendritic cells
(classical DC are in the T cell zone of the lymph nodes to be able to interact)
describe the capture and presentation of antigens by dendritic cells
- immature DC capture protein antigen
- DC are activated via PRR and migrate to lymph node via chemokine gradient
- mature DC present antigens to T cells (finish maturation in the lymph node)
what makes dendritic cells the most potent APC for activating naive T cells?
They constitutively express Class II MHC and costimulators, and also increases with maturation. They don’t need to be activated to be able to present class II MHC.
(macrophages and B lymphocytes have low or negative levels, or need to be induced)
What determines the specific recognition of antigens?
Major histocompatibility complex (MHC) molecules
describe the genes of MHC locus
- human MHC proteins are called human leukocyte antigens (HLA)
- two sets of highly polymorphic genes: Class I MHC genes and Class II MHC genes (each has its own locus)
- other nonpolymorphic genes associated with antigen presentation, cytokine, and complement
What are HLA A9 and B15 associated with?
These are MHC class I molecules associated with aggressive periodontitis
describe the structure of MHC class I molecules
- membrane proteins containing a peptide-binding cleft at the amino terminal
- 8-11 AA peptide can be accommodated
- alpha chain associated with b2-microglobulin with a groove accommodating 8-11 AA: variability in a1 and a2, a3 is invariant
Structure of MHC class II molecules
- membrane proteins containing a peptide-binding cleft at the amino terminal
- 10-20 AA peptide
- a and b chain with a groove accommodating 10-30 AA, variability in a1 and b1, a2 and b2 invariant
Describe the MHC I and T cell receptor interaction
- CD8 cells only recognize peptides presented by MHC class I
- a3 binds CD8 on CD8 cells
- peptide binds floor of the cleft while TCR binds side and top of cleft
Describe the MHC II and T cell receptor interaction
- CD4 T cells only recognize peptides presented by MHC class II
- b2 binds CD4 on CD4 T cells
- peptide binds floor of the cleft while TCR binds side and top of cleft
MHC haplotype
The set of MHC alleles on each chromosome inherited from both parents
- 6 different class I
- 6-8 different class II
MHC polymorphism ensures…
that a population can deal with microbe diversity (many different alleles present in the population; different individuals are able to respond to different microbial peptides)
Which cells express Class II MHC?
Dendritic cells, macrophages, B cells (APCs) and induced by IFNgama. Thus CD4+ helper T lymphocytes will interact with these APCs.
Which cells express Class I MHC?
Expressed on all nucleated cells. Thus CD8+ CTLs can kill any type of virus-infected cell
describe the binding structure of peptides to MHC molecules
Anchor residues in the peptide anchor the peptide to the groove of MHC molecules. Other residues are recognized by TCR
Features of peptide binding to MHC molecules
- different peptides can bind to the same MHC (not as specific as T cell receptor)
- one binding cleft = each MHC molecule presents only one peptide at a time
- one APC displays a large number of different peptides (increases probability of presenting to T cells in lymph node or spleen)
- T cell receptors only bind peptides (protein antigens) thus not carbs, lipids, etc.
- peptides are loaded on MHC during MHC assembly
- loading of peptides stabilizes expression of MHC on cell surface
- binding lasts for several days to maximize interactions with T cells
How are proteins converted into peptides?
antigen processing pathways
(overview) What is the processing pathway of extracellular and cytosolic protein antigens in MHC Class II?
Extracellular proteins are processed in endosome/lysosome and displayed on MHC Class II to CD4 cells
(overview) What is the processing pathway of cytosolic protein antigens in MHC Class I?
Cytosolic proteins are processed by proteasome and endoplasmic reticulum and displayed on MHC Class I to CD8 cells
What may be an extracellular protein that will be used in a class II MHC?
A cell that is being phagocytosed, a dead cell containing a molecule like a virus
(in-detail) Describe the processing of extracellular proteins for Class II MHC
- antigen internalization: uptake of extracellular proteins into vesicular compartments of APC
- antigen degradation in lysosome: processing of internalized proteins in endosomal/lysosomal vesicles. Biosynthesis and transport of class II MHC molecules to endosomes.
- antigen association with Class II molecules: association of processed peptides with class II MHC molecules in vesicles. Expression of peptide-MHC complexes on cell surface.
What may be an intracellular protein used in a Class I MHC?
Virus in the cytoplasm
(in-detail) Describe the processing of intracellular proteins for Class I MHC
- Protein antigen tagging with ubiquitin
- Antigen degradation by proteasome (recognized due to ubiquitin tagging) and transport via TAP in ER
- Peptide is loaded onto MHC Class I; antigen association with Class I molecules and surface expression
What is the significance of MHC-associated antigen presentation?
- optimization of response to different microbes in different locations (ex1: T cell interacting with macrophage that has phagocytosed an extracellular microbe. The T cell can produce cytokines like interferon-gamma that helps the macrophage to get activated and kill the phagocytosed microbe. Macrophage will ingest the microbe but need a signal to actually kill it. Ex2: Same situation with B cells, except T cell cytokine activates the B cell to make an antibody against the antigen. Ex3: Cytotoxic T cells will be able to kill antigen-expressing target cells once activated by APC)
- microbes can be extracellular and become intracellular
CD4+ cells
Helper T cells
CD8+ cells
Cytotoxic T cells that recognize non-self (viral or malignant) proteins on MHC I of nucleated cells. Release porforins and granzymes to induce apoptosis
How are internalized microbial proteins presented to T cells?
Processed in the endosome and loaded onto MHC Class II for presentation to CD4 T cells.
Describe the inflammatory mechanisms leading to bone loss in periodontitis
Mice deficient in MHC Class II-restricted CD4 T cells are resistant to experimental periodontitis, thus activated CD4 T cells mediate destructive inflammation in the periodontium
Antigens are transported from _______/_______ to __________ where recognition by T cells occurs
tissue/mucosa; lymphoid organs
The majority of DC in tissues and lymphoid organs are what?
Classical DC
Describe the capture and presentation of antigens by DC
-Immature DC captures and processes protein antigen
-DC are activated via PRR and migrate to LN via chemokine gradient (upregulate chemokine receptors (CCR7) and costimulatory molecules).
-Mature DC presents protein antigens to T cells
Where do peptides bind?
IN the cleft (of MHC and TCR)
T cell recognizes _______ ________ displayed by MHC molecules on APC
peptide antigens
How many sets of genes?
Two sets of highly polymorphic genes
-Class I MHC genes
-Class II MHC genes
Describe the structure of MHC class I molecules
-Membrane proteins containing a peptide-binding cleft at the amino-terminal
-Alpha chain associated with beta2-microglobulin
Describe the structure of MHC class II molecules
-Membrane proteins containing a peptide-binding cleft at the amino terminal
-Alpha and Beta chains
_____ T cells only recognize peptides presented by MHC class I
CD8
alpha3 (invariant portion of alpha chain) binds CD8 on CD8 T cells
_____ T cells only recognize peptides presented by MHC class II
CD4
beta2 (invariant portion of beta chain) binds CD4 on CD4 T cells
Why is MHC polymorphism important?
It ensures that a population can deal with microbe diversity
Where is MHC Class II expressed?
On APC and induced by IFNgamma
Where is MHC Class I expressed?
On all nucleated cells
What can MHC molecules bind to?
Proteins, Lipids, Carbohydrate sugars, and Nucleic acids
What can T cells recognize?
They can only recognize peptides derived from protein antigens
When peptides bind to MHC, how long does binding last?
Binding lasts up to days to maximize interaction with T cells
Describe processing of extracellular proteins
Extracellular proteins (tumor, bacteria) are processed in endosome/lysosome and peptides displayed on MHC Class II to CD4 cells
Describe processing of cytosolic proteins
Cytosolic proteins (virus, bacteria that escape phagosome) are processed by proteasome and endoplasmic reticulum and peptides displayed on MHC Class I to CD8 cells
What is the significance of MHC-associated antigen presentation?
Optimization of response to different microbes in different locations
-extracellular –> CD4
-intracellular –> CD8
