Topic 9 Antigen Processing and Presentation

Introduction

Previously we have described the key functions of molecules coded by the major histocompatibility complex (MHC). In this lesson we will look at the two ways in which foreign antigens are processed prior to presentation to the cells of the immune system. The foreign antigens that trigger an immune response are of two distinct types. First, there are the antigens derived from organisms such as bacteria that, when they enter the body, are phagocytosed by cells such as macrophages. These antigens may also be found free in the circulation for a time. These are called exogenous antigens and are processed by specialized antigen processing cells such as macrophages. A second type of antigen is actually made within the body fluid. Thus if a virus invades a cell and takes over its biosynthetic process, then new viral proteins are formed within the infected cell. These are called endogenous antigens. Endogenous antigens are presented to antigen-sensitive cells by the cells in which they are formed. In this section the mechanism of antigen processing and the means by which processed antigen and MHC molecules are combined within different intracellular compartments for presentation are examined in more detail.

Objectives

On completion of this section and the required reading, you should be able to:

n describe self MHC restriction;

n compare the cytosolic pathway for antigen presentation with the endocytic pathway for antigen presentation;

n compare professional with non professional antigen presenting cells;

n draw a flow diagram comparing cytosolic and endocytic pathways for processing antigens;

n describe peptide generation by proteosomes;

n describe transport of antigenic peptides from the cytosol to the Rough Endoplasmic reticulum;

n draw a concept map for the separate antigen presenting pathways for endogenous and exogenous antigen;

n describe the assembly of MHC-II molecules within the Rough endoplasmic reticulum;

n describe the development of a viral vaccine that uses the cytosolic pathway;

n describe the development of a vaccine that uses the endocytic pathway.

Required Reading

Please refer to the textbook key for specific readings for this section.

P Key Words

• antigen presenting cells • professional antigen presenting cells • nonprofessional antigen presenting cells • cytosolic pathway • endocytic pathway • ubiquitin

• proteosome • transporters associated with antigen processing (TAP) • molecular chaperone • calnexin • invariant chain • CLIP

P Key Concepts

n Foreign antigens must be specially processed before they can be presented to the antigen-sensitive cells of the immune system.

n The most important antigen processing cells are macrophages, dendritic cells, and B-cells

n Antigen fragments generated inside these cells are bonded to specialized receptors called MHC molecules in the cell cytoplasm and then transported to the surface of antigen-presenting cells.

n Foreign, phagocytosed antigens, called exogenous antigens, are fragmented in endosomes and the fragment attached to MHC class II molecules.

n Foreign molecules synthesized within a cell (as in a virus-infected cell) are attached to MHC class I molecules while they are being synthesized

DID YOU KNOW?

How the Immune System fights Leishmania

Throughout the world infectious diseases have always been the leading cause of human death. Our bodies are equipped with multiple mechanisms and levels of defense offered by the immune system. The antibodies, are especially effective at destroying bacteria that live outside the human cell. The white blood cells known as CD8 T lymphocytes, routes pathogens such as viruses that associate intimately with the cellular machinery of the host. CD4 T lymphocytes are of central importance in defeating the bacteria and other parasites that live within cells.

Visceral and cutaneous leishmaniasis, a disease caused by Leishmania, is a common ailment in much of the developing world. Studies involving this parasitic protozoa allowed understanding of how the immune system fights intracellular infections:

The primary target of the Leishmania parasites the macrophage. During their routine scavenging in the bloodstream, macrophages engulf Leishmania organisms and package them in vacuoles. Those vacuoles fuse with others that contain proteolytic enzymes that can kill and digest most m71

icrobes. Leishmania, however differentiate into a new form that not only can endure this chemical assault but actually can thrive during it. The parasites multiply inside the vacuole until the infected macrophage host can no longer sustain them all and dies.

Fortunately, the body has a method for eliminating intracellular parasites sequestered in this way. MHC molecules can bind to peptides produced within the cell and bring them to the cell surface, where they can be recognized by the immune system. In case of Leishmania infections of macrophages, it’s the class II MHC molecules that pick up peptides from the microbes. Class II MHC molecules are imported into the vacuoles containing the Leishmania organisms and other extracellular antigens ingested by the macrophages. The MHC molecules become loaded with peptides shed by the parasites or cleaved from them by the proteolytic enzymes. Not all the peptides present will be able to associate with the class II MHC molecules, but from an antigen as complex as Leishmania, at least several will. These complexes of MHC molecules and peptides then move to the macrophage’s outer membrane.

Once displayed on the surface, the complexes can alert passing CD4 T-cells to the presence of the intracellular infection. The great diversity of receptors made by the T cell population ensures that a match can be found for virtually any peptide-MHC combination. Thus, with the help of MHC molecules, T cells can recognize antigens from pathogens that hide inside cells. This recognition event develops into an immunologic response if the macrophage also provides an additional signal to the T cell. One surface molecule, which will be discussed in more detail in the next lesson, is B7. Macrophages and similar cells express it when become infected. B7 is recognized by a separate protein, CD28, on the T cell’s surface. Interactions both between the T cell receptor and the MHC II, and between B7 and CD28 are necessary for the CD4 T cells to mobilize an optimal response.

Infectious Diseases and the Immune System. W.E. Paul, In: Life, Death and the Immune System. Scientific American: A Special Issue, W.H. Freeman and Company, New York, 1994

Review Questions

1. Textbook Study Questions

Review questions at the end of the Chapter 10. The answers with explanations are available at the end of the textbook.

2. Multiple Choice Questions

1. Exogenous antigen processing mainly occurs within

A) T lymphocytes

B) neutrophils

C) plasma cells

D) macrophages

E) none of the above

2. Endogenous antigens are antigens that are

A) adsorbed onto cell surfaces

B) phagocytosed by macrophages

C) recognized by B cells

D) recognized by CD4 positive cells

E) synthesized within cells

3. Proteasomes play a key role in processing

A) exogenous antigens

B) bacterial antigens

C) cell surface antigens

D) endogenous antigens

E) MHC class II peptides

3. Definitions/Short Answer Questions.

1. Name thee types of professional APCs.

2. For each type indicate whether it expresses MHC-II molecules and a co-stimulatory signal constitutively or must be activated before doing so.

3. Describe the role of ubiquitin in the processing of endogenous antigens.

4. Describe the role of calnexin in the assembly of MHC-I.

5. T cells can react only with protein fragments.

What is this process called?

How does it occur?

Which pathway leads to antigen interaction with MHC-I molecules?

Which pathway leads to interaction with MHC-II molecules?

Where to Go from Here

Once you have completed the review, take some time and complete the objectives. If you are having trouble with any of the concepts, contact your instructor.

Remember to regularly check your Instructor Assignment Information for assignments and due dates for completing them.

When you are confident that you can complete the objectives, proceed to the next topic.