HLA Proteins and Antigen Presentation
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HLA Proteins and Antigen 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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@HandierMesa

Questions and Answers

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?

<p>It binds to the ⍺3 subunit of HLA class I proteins.</p> Signup and view all the answers

What is the role of the β2 microglobulin subunit in HLA class I proteins?

<p>It is not covalently bound to the heavy chain and is necessary for proper folding.</p> Signup and view all the answers

What is the length of antigens bound by HLA-I?

<p>8-10 amino acids long</p> Signup and view all the answers

Which type of cells exclusively express HLA-2?

<p>Antigen presenting cells</p> Signup and view all the answers

Which of the following antigen presenting cells constitutively express high levels of HLA-2?

<p>Dendritic cells</p> Signup and view all the answers

Which type of antigen presenting cells need to be activated before they express HLA-2?

<p>Macrophages</p> Signup and view all the answers

What is a characteristic of non-professional antigen presenting cells in terms of HLA-2 expression?

<p>They only express HLA-2 under particular conditions</p> Signup and view all the answers

What is the function of HLA-2 in antigen presenting cells?

<p>To co-stimulate helper-T-cells</p> Signup and view all the answers

Which of the following is NOT a type of professional antigen presenting cell?

<p>Fibroblasts</p> Signup and view all the answers

What is the primary source of the antigenic peptide in the endogenous pathway?

<p>The cytosol</p> Signup and view all the answers

What is the primary function of immunoproteosomes in antigen processing?

<p>To present peptides to T-cells</p> Signup and view all the answers

What happens to the peptide after it is derived from proteasomal degradation?

<p>It is transported into the RER and loaded onto the HLA-1 protein</p> Signup and view all the answers

What is the primary function of HLA-1 proteins?

<p>To bind intracellular antigens via the endogenous pathway</p> Signup and view all the answers

What is the difference between HLA-1 molecules expressed during viral infection and those expressed during normal conditions?

<p>Some HLA-1 molecules express viral peptides, while others express host peptides</p> Signup and view all the answers

What is the result of the endogenous pathway of antigen processing?

<p>The loaded HLA-1 is then expressed on the cell surface</p> Signup and view all the answers

What is the purpose of proteasomal degradation in antigen processing?

<p>To derive antigenic peptides from foreign/altered proteins or normal self-antigens</p> Signup and view all the answers

What is the significance of HLA-1 molecules expressing self-antigens?

<p>It inhibits an immune response against the self-antigens</p> Signup and view all the answers

What is necessary for HLA-2 proteins to bind extracellular antigens via the exogenous pathway?

<p>Up-regulation of phagocytosis</p> Signup and view all the answers

Which cytokine is particularly good at up-regulating HLA-2 expression?

<p>Interferon-gamma</p> Signup and view all the answers

What is the role of phagocytosis in the exogenous pathway?

<p>To provide peptides for loading onto HLA-2</p> Signup and view all the answers

What is the role of HLA-DM in antigen processing?

<p>It helps with loading of antigens onto HLA-2</p> Signup and view all the answers

In which cells does IL-4 up-regulate HLA-2 expression?

<p>B-cells</p> Signup and view all the answers

What is the result of phagocytosis in the exogenous pathway?

<p>Antigen is loaded onto HLA-2</p> Signup and view all the answers

Where are HLA class I molecules typically found?

<p>In the endoplasmic reticulum</p> Signup and view all the answers

Under what circumstances can exogenous antigens be presented by HLA class I molecules?

<p>During cross-presentation</p> Signup and view all the answers

What is the fate of the antibody after receptor-mediated endocytosis in B-cells?

<p>It is recycled back to the surface of the cell</p> Signup and view all the answers

What happens to viral particles in the cytosol of an infected cell that is phagocytosed?

<p>They are presented on HLA class II molecules of the phagocyte</p> Signup and view all the answers

How do HLA class I and HLA class II molecules differ in terms of antigen processing?

<p>HLA class I molecules process antigens from the cytosol, while HLA class II molecules process antigens from the extracellular environment</p> Signup and view all the answers

What is the role of HLA-2 proteins in the exogenous pathway?

<p>To bind extracellular antigens</p> Signup and view all the answers

What is necessary for HLA-2 proteins to express antigens on the surface of the cell?

<p>Loading of peptides onto HLA-2</p> Signup and view all the answers

What determines whether antigenic peptides associate with HLA class I or HLA class II molecules?

<p>The mode of antigen entry into cells and the site of antigen processing</p> Signup and view all the answers

Where are HLA class II molecules typically found?

<p>In endocytic compartments</p> Signup and view all the answers

What is the result of interferon-gamma on HLA-2 expression in B-cells?

<p>Down-regulation of HLA-2</p> Signup and view all the answers

What is the role of HLA-DO in antigen processing?

<p>It inhibits the loading of antigens onto HLA-2</p> Signup and view all the answers

What is the function of the invariant chain in the RER?

<p>To prevent cytosolic antigens from being loaded onto HLA-2 proteins</p> Signup and view all the answers

What happens to the invariant chain when the HLA-2 containing vesicle merges with the phagosome/endosome?

<p>It is chopped up into CLIP</p> Signup and view all the answers

What is required for a peptide to bind to HLA-2 proteins?

<p>High affinity and displacement of CLIP</p> Signup and view all the answers

What is the final step in the exogenous pathway of antigen processing?

<p>Expression of HLA-2 proteins on the cell surface</p> Signup and view all the answers

What is the purpose of CLIP in the exogenous pathway?

<p>To prevent the binding of peptides to HLA-2 proteins</p> Signup and view all the answers

In which compartment do HLA-2 proteins associate with the invariant chain?

<p>RER</p> Signup and view all the answers

What is the fate of CLIP after a peptide binds to HLA-2 proteins?

<p>It is displaced</p> Signup and view all the answers

What is the role of the invariant chain in preventing the loading of cytosolic antigens onto HLA-2 proteins?

<p>It binds to HLA-2 proteins and prevents antigen loading</p> Signup and view all the answers

What is the primary function of HLA proteins in antigen presentation?

<p>To facilitate the interaction between T-cells and antigens</p> Signup and view all the answers

Which type of cells can present antigens using HLA proteins?

<p>A wide variety of cells</p> Signup and view all the answers

What is the key difference between HLA-1 and HLA-2 proteins?

<p>HLA-1 binds to endogenous antigens, while HLA-2 binds to exogenous antigens</p> Signup and view all the answers

What is the purpose of antigen presentation in T-cell activation?

<p>To activate T-cells against foreign antigens</p> Signup and view all the answers

What is cross-presentation, and which cells can perform it?

<p>The presentation of exogenous antigens to T-cells, and dendritic cells and macrophages can perform it</p> Signup and view all the answers

What is the role of HLA proteins in distinguishing between foreign and self antigens?

<p>To help T-cells distinguish between foreign and self antigens</p> Signup and view all the answers

What is the result of antigen presentation in T-cell activation?

<p>T-cell activation</p> Signup and view all the answers

Which of the following is a characteristic of HLA proteins?

<p>They are not genetically shuffled like lymphocyte receptors</p> Signup and view all the answers

What is the function of HLA-DM in antigen processing?

<p>To help with the loading of antigens onto HLA-2</p> Signup and view all the answers

What is the primary function of HLA-1 molecules on the surface of a cell?

<p>To bind a CD8+ T-cells Cytotoxic T cell and activate it</p> Signup and view all the answers

Where do antigens processed in the exogenous pathway associate with?

<p>HLA class II molecules in endocytic compartments</p> Signup and view all the answers

Under what circumstances can exogenous antigens be presented by HLA class I molecules?

<p>During cross-presentation</p> Signup and view all the answers

Which type of cytokines can increase the expression of HLA-1 molecules?

<p>Type 1 and type 2 interferons, and tumour necrosis factor alpha</p> Signup and view all the answers

What happens to viral particles in the cytosol of an infected cell that is phagocytosed?

<p>They are presented on HLA-2 molecules</p> Signup and view all the answers

What is the source of cytokines that increase HLA-1 expression?

<p>Local antigen-presenting cells and later activated T-helper cells</p> Signup and view all the answers

What determines whether antigenic peptides associate with HLA class I or HLA class II molecules?

<p>The mode of antigen entry into cells and the site of antigen processing</p> Signup and view all the answers

What is the function of activated cytotoxic T-cells?

<p>To kill infected cells by inducing apoptosis</p> Signup and view all the answers

What is the role of HLA-DO in antigen processing?

<p>To inhibit the loading of antigens onto HLA-2</p> Signup and view all the answers

What type of pathway is involved in the presentation of antigens by HLA-1 molecules?

<p>Endogenous pathway</p> Signup and view all the answers

What is the source of interferon-gamma in the context of HLA-1 expression?

<p>Activated T-helper cells</p> Signup and view all the answers

What is the significance of HLA-2 molecules in antigen processing?

<p>They present antigens to CD4+ T-cells</p> Signup and view all the answers

What is the result of phagocytosis in the exogenous pathway?

<p>Antigens are presented on HLA-2 molecules</p> Signup and view all the answers

What is the primary function of immunoproteosomes in antigen processing?

<p>To substitute different subunits into the regular proteosome</p> Signup and view all the answers

Which cytokines can induce the substitution of different subunits into the regular proteosome?

<p>IFN-gamma and TNF-alpha</p> Signup and view all the answers

What is the role of TAP in antigen processing?

<p>To translocate the peptide fragment into the RER for loading onto HLA-1</p> Signup and view all the answers

What is the result of immunoproteosomes substituting different subunits into the regular proteosome?

<p>The production of peptides that bind with high affinity to HLA-1</p> Signup and view all the answers

Why are some viruses able to block the expression of their viral peptides on the surface of infected cells?

<p>Because they can block TAP</p> Signup and view all the answers

What is necessary for the loading of peptides onto HLA-1?

<p>The presence of ATP</p> Signup and view all the answers

What is the result of the endogenous pathway of antigen processing?

<p>The presentation of antigens to T-cells</p> Signup and view all the answers

Which type of cells express HLA-1?

<p>All cells, as part of the endogenous pathway</p> Signup and view all the answers

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.

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