75 Questions
What is implied about the binding of antigens to proteins based on the text?
Antigens are not bound tightly to proteins.
What is a characteristic of MHC-like proteins?
They have a wide range of functions beyond presenting antigens.
What is a key difference between HLA class I and HLA class II proteins?
HLA class I interacts with cytotoxic T-cells, while HLA class II interacts with T-helper cells.
What is the function of the CD8 co-receptor on cytotoxic T-cells?
It binds to the ⍺3 subunit of HLA class I proteins.
What is the role of the β2 microglobulin subunit in HLA class I proteins?
It is not covalently bound to the heavy chain and is necessary for proper folding.
What is the length of antigens bound by HLA-I?
8-10 amino acids long
Which type of cells exclusively express HLA-2?
Antigen presenting cells
Which of the following antigen presenting cells constitutively express high levels of HLA-2?
Dendritic cells
Which type of antigen presenting cells need to be activated before they express HLA-2?
Macrophages
What is a characteristic of non-professional antigen presenting cells in terms of HLA-2 expression?
They only express HLA-2 under particular conditions
What is the function of HLA-2 in antigen presenting cells?
To co-stimulate helper-T-cells
Which of the following is NOT a type of professional antigen presenting cell?
Fibroblasts
What is the primary source of the antigenic peptide in the endogenous pathway?
The cytosol
What is the primary function of immunoproteosomes in antigen processing?
To present peptides to T-cells
What happens to the peptide after it is derived from proteasomal degradation?
It is transported into the RER and loaded onto the HLA-1 protein
What is the primary function of HLA-1 proteins?
To bind intracellular antigens via the endogenous pathway
What is the difference between HLA-1 molecules expressed during viral infection and those expressed during normal conditions?
Some HLA-1 molecules express viral peptides, while others express host peptides
What is the result of the endogenous pathway of antigen processing?
The loaded HLA-1 is then expressed on the cell surface
What is the purpose of proteasomal degradation in antigen processing?
To derive antigenic peptides from foreign/altered proteins or normal self-antigens
What is the significance of HLA-1 molecules expressing self-antigens?
It inhibits an immune response against the self-antigens
What is necessary for HLA-2 proteins to bind extracellular antigens via the exogenous pathway?
Up-regulation of phagocytosis
Which cytokine is particularly good at up-regulating HLA-2 expression?
Interferon-gamma
What is the role of phagocytosis in the exogenous pathway?
To provide peptides for loading onto HLA-2
What is the role of HLA-DM in antigen processing?
It helps with loading of antigens onto HLA-2
In which cells does IL-4 up-regulate HLA-2 expression?
B-cells
What is the result of phagocytosis in the exogenous pathway?
Antigen is loaded onto HLA-2
Where are HLA class I molecules typically found?
In the endoplasmic reticulum
Under what circumstances can exogenous antigens be presented by HLA class I molecules?
During cross-presentation
What is the fate of the antibody after receptor-mediated endocytosis in B-cells?
It is recycled back to the surface of the cell
What happens to viral particles in the cytosol of an infected cell that is phagocytosed?
They are presented on HLA class II molecules of the phagocyte
How do HLA class I and HLA class II molecules differ in terms of antigen processing?
HLA class I molecules process antigens from the cytosol, while HLA class II molecules process antigens from the extracellular environment
What is the role of HLA-2 proteins in the exogenous pathway?
To bind extracellular antigens
What is necessary for HLA-2 proteins to express antigens on the surface of the cell?
Loading of peptides onto HLA-2
What determines whether antigenic peptides associate with HLA class I or HLA class II molecules?
The mode of antigen entry into cells and the site of antigen processing
Where are HLA class II molecules typically found?
In endocytic compartments
What is the result of interferon-gamma on HLA-2 expression in B-cells?
Down-regulation of HLA-2
What is the role of HLA-DO in antigen processing?
It inhibits the loading of antigens onto HLA-2
What is the function of the invariant chain in the RER?
To prevent cytosolic antigens from being loaded onto HLA-2 proteins
What happens to the invariant chain when the HLA-2 containing vesicle merges with the phagosome/endosome?
It is chopped up into CLIP
What is required for a peptide to bind to HLA-2 proteins?
High affinity and displacement of CLIP
What is the final step in the exogenous pathway of antigen processing?
Expression of HLA-2 proteins on the cell surface
What is the purpose of CLIP in the exogenous pathway?
To prevent the binding of peptides to HLA-2 proteins
In which compartment do HLA-2 proteins associate with the invariant chain?
RER
What is the fate of CLIP after a peptide binds to HLA-2 proteins?
It is displaced
What is the role of the invariant chain in preventing the loading of cytosolic antigens onto HLA-2 proteins?
It binds to HLA-2 proteins and prevents antigen loading
What is the primary function of HLA proteins in antigen presentation?
To facilitate the interaction between T-cells and antigens
Which type of cells can present antigens using HLA proteins?
A wide variety of cells
What is the key difference between HLA-1 and HLA-2 proteins?
HLA-1 binds to endogenous antigens, while HLA-2 binds to exogenous antigens
What is the purpose of antigen presentation in T-cell activation?
To activate T-cells against foreign antigens
What is cross-presentation, and which cells can perform it?
The presentation of exogenous antigens to T-cells, and dendritic cells and macrophages can perform it
What is the role of HLA proteins in distinguishing between foreign and self antigens?
To help T-cells distinguish between foreign and self antigens
What is the result of antigen presentation in T-cell activation?
T-cell activation
Which of the following is a characteristic of HLA proteins?
They are not genetically shuffled like lymphocyte receptors
What is the function of HLA-DM in antigen processing?
To help with the loading of antigens onto HLA-2
What is the primary function of HLA-1 molecules on the surface of a cell?
To bind a CD8+ T-cells Cytotoxic T cell and activate it
Where do antigens processed in the exogenous pathway associate with?
HLA class II molecules in endocytic compartments
Under what circumstances can exogenous antigens be presented by HLA class I molecules?
During cross-presentation
Which type of cytokines can increase the expression of HLA-1 molecules?
Type 1 and type 2 interferons, and tumour necrosis factor alpha
What happens to viral particles in the cytosol of an infected cell that is phagocytosed?
They are presented on HLA-2 molecules
What is the source of cytokines that increase HLA-1 expression?
Local antigen-presenting cells and later activated T-helper cells
What determines whether antigenic peptides associate with HLA class I or HLA class II molecules?
The mode of antigen entry into cells and the site of antigen processing
What is the function of activated cytotoxic T-cells?
To kill infected cells by inducing apoptosis
What is the role of HLA-DO in antigen processing?
To inhibit the loading of antigens onto HLA-2
What type of pathway is involved in the presentation of antigens by HLA-1 molecules?
Endogenous pathway
What is the source of interferon-gamma in the context of HLA-1 expression?
Activated T-helper cells
What is the significance of HLA-2 molecules in antigen processing?
They present antigens to CD4+ T-cells
What is the result of phagocytosis in the exogenous pathway?
Antigens are presented on HLA-2 molecules
What is the primary function of immunoproteosomes in antigen processing?
To substitute different subunits into the regular proteosome
Which cytokines can induce the substitution of different subunits into the regular proteosome?
IFN-gamma and TNF-alpha
What is the role of TAP in antigen processing?
To translocate the peptide fragment into the RER for loading onto HLA-1
What is the result of immunoproteosomes substituting different subunits into the regular proteosome?
The production of peptides that bind with high affinity to HLA-1
Why are some viruses able to block the expression of their viral peptides on the surface of infected cells?
Because they can block TAP
What is necessary for the loading of peptides onto HLA-1?
The presence of ATP
What is the result of the endogenous pathway of antigen processing?
The presentation of antigens to T-cells
Which type of cells express HLA-1?
All cells, as part of the endogenous pathway
Study Notes
HLA Proteins
- HLA proteins are not bound tightly to antigens, allowing them to present a wide variety of antigens to a wide variety of lymphocytes.
- There are also a wide variety of genes/proteins called "MHC-like" that have a range of functions beyond simply presenting antigens.
HLA Class I and II Proteins
- HLA Class I proteins:
- Interact with cytotoxic T-cells and bind intracellular antigens.
- Interact with a CD8 co-receptor on the cytotoxic T-cell.
- HLA Class II proteins:
- Interact with T-helper cells and bind extracellular antigens.
- Interact with a CD4 co-receptor on the T-helper cell.
HLA-I Structure
- The antigen binding site is found between the α1 and α2 subunits of the glycoprotein heavy chain.
- The CD8 co-receptor on the cytotoxic T-cell binds to the α3 subunit.
- β2 microglobulin subunit is not covalently bound to the heavy chain and is needed for proper folding.
HLA-1 Expression and Function
- HLA-1 proteins bind intracellular antigens via the endogenous pathway.
- Most of the time, these are self-antigens, but in the case of infection or malignancy, the peptide can be foreign.
- During viral infection, some HLA-1 molecules on a cell will express viral peptides, while some will express host peptides.
HLA-1 Expression: Endogenous Pathway
- Antigen processing:
- Source of the antigenic peptide is from the cytosol.
- The peptide is derived from proteasomal degradation of foreign/altered proteins (or normal self-antigens).
- The peptide is then transported into the RER and loaded onto the HLA-1 protein.
- The loaded HLA-1 is then expressed on the cell surface.
HLA-2 Expression and Function
- HLA-2 types are expressed exclusively on antigen presenting cells (APCs).
- APCs include:
- Dendritic cells
- Macrophages
- B-cells
- Non-professional APCs (e.g. fibroblasts, glial cells, pancreatic beta cells, thymic epithelial cells, intraepithelial lymphocytes, vascular endothelial cells)
- However, some of these APCs won't even express HLA-2 unless they've been activated.
HLA-2 Expression: Exogenous Pathway
- HLA-2 proteins bind extracellular antigens via the exogenous pathway.
- Phagocytosis needs to be upregulated in concurrence with HLA-2 expression.
- Phagocytosis is the source of the peptides that are loaded onto the HLA-2.
- Phagocytosis can occur through the "regular" pathway or antibody-mediated in the case of B-cells.
Antigen Processing Exceptions
- Exogenous antigens can be presented by HLA-1, and endogenous antigens can be presented by HLA-2 in some circumstances.
- For example, an infected cell dies and is phagocytosed, and viral particles in the cytosol of the infected cell will be presented on HLA-2 of the phagocyte.
HLA-2 Expression: Exogenous Pathway
- HLA-2 proteins bind extracellular antigens via the exogenous pathway.
- In the RER, HLA-2 protein associates with the invariant chain (CD74) to prevent cytosolic antigens from being loaded onto HLA-2.
- As the HLA-2 containing vesicle merges with the phagosome/endosome containing the antigen, the invariant chain is chopped up into a "chopped version" called CLIP.
- CLIP remains bound to the HLA-2 peptide binding region until displaced by a peptide with sufficient affinity to HLA-2.
- When a peptide binds with sufficient affinity to HLA-2, CLIP is displaced, and HLA-2 with bound extracellular antigen is expressed on the surface of the cell.
Overview of Antigen Presentation
- Antigen presentation is necessary for T-cell activation.
- HLA proteins present antigens to T-cells in a specific fashion.
- Antigens must be presented to a T-cell in order for them to recognize the antigen.
- HLA proteins help a T-cell distinguish between foreign and self-antigens.
T-Cells and Antigen – Necessity of HLA
- A wide variety of cells can present antigens using HLA proteins.
- HLA proteins are bound to antigens, but are not genetically "shuffled" like lymphocyte receptors.
HLA-1 Expression: Endogenous Pathway
- Antigen processing occurs via the endogenous pathway.
- The protein that translocates the peptide fragment into the RER for loading onto HLA-1 is called TAP.
- Cytokines can increase the expression of HLA-1 molecules.
- Tumour necrosis factor alpha (TNFα) and type 1 interferons (IFN) can increase HLA-1 expression.
HLA-1 – What Happens Next
- Once a peptide-bound HLA-1 is expressed on the surface of a cell, it can bind to a CD8+ T-cell and activate it.
- Activated cytotoxic T-cells can kill infected cells by inducing apoptosis.
HLA Types Summary
- HLA-1: presents intracellular antigens to CD8+ T-cells via the endogenous pathway.
- HLA-2: presents extracellular antigens to CD4+ T-cells via the exogenous pathway.
Antigen-Processing Exceptions
- Exogenous antigens can be presented by HLA-1, and endogenous antigens can be presented by HLA-2 in some circumstances, such as cross-presentation.
Learn about the role of HLA proteins in presenting antigens to lymphocytes, their types, and functions. Understand HLA class I and II proteins and their interactions with immune cells.
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