L7: Antigen Processing and Presentation

Question 1

How do B cells “see” antigen?

Answer 1

Antibody on B cells or free antibody can recognize intact antigen (i.e. soluble antigens and cell surface antigens)

Proteins, nucleic acids, polysaccharides, lipids, and small molecules are antigenic for B cells

Can recognize conformation or linear epitopes: consecutive amino acids on a denatured protein would be a linear epitope; a 3-D structure would be a conformational epitope (could even be non-contiguous amino acids when they start to overlap)

Question 2

How to T cells “see” antigen?

Answer 2

Recognize protein antigens as discrete peptides

Recognize linear epitopes (don’t recognize non-contiguous epitopes)

Recognize antigen only when it is bound to MHC

Question 3

How do CD8+ cytotoxic cells “see” antigen? How do they respond?

Answer 3

“See” antigen complexed to MHC class I and respond by killing the infected cell

Question 4

How do CD4+ helper cells “see” antigen? How do they respond?

Answer 4

“See” antigen complexed to MHC class II and respond by proliferation and production of cytokines

Question 5

What must APCs express in order for T cell to recognize and respond to a foreign peptide antigen?

Answer 5

APC must express MHC molecules that are recognized as self

Question 6

What are “self” MHC?

Answer 6

Those MHC antigens that the T cell encountered during development in the thymus

Question 7

What are cytosolic pathogens presented to?

Answer 7

Presented to effector CD8 T cells

Effect is cell death

Question 8

What are intravesicular pathogens presented to?

Answer 8

Presented to effector CD4 T cells

Effect is activation to kill intravesicular bacteria and parasites

Question 9

What are extracellular pathogens and toxins presented to?

Answer 9

Presented to effector CD4 T cells

Effect is activation of B cells to secrete Ig to eliminate extracellular bacteria/toxins

Question 10

What recognizes exogenous antigens?

Answer 10

CD4 cells

These antigens are processed and presented w/ MHC class II

The CD4+ T cells respond with proliferation and cytokine production

Question 11

What are the professional antigen presenting cells? What do they do?

Answer 11

Dendritic cells

Macrophages

B cells

Either express constitutive MHC class II or very easily upregulate it

Antigen presenting cells are those special cells that can provide the high levels of MHC and co-stimulatory molecules required for T cell activation

Question 12

What is the response of dendritic cell antigen uptake?

Answer 12

Naive T cell activation: clonal expansion and differentiation into effector T cells

Question 13

What is the response of macrophage antigen uptake?

Answer 13

Effector T cell activation: activation of macrophages (cell-mediated immunity)

Question 14

What is the response of B cell antigen uptake?

Answer 14

Effector T cell activation: B cell activation and antibody production (humoral immunity)

Question 15

Where are dendritic cells found?

Answer 15

Found at all of the sites where there will be antigen entry

Skin: Langerhans cells and layer of dermal dendritic cells

GI tract

Respiratory tract

Question 16

What occurs if antigen enters blood stream?

Answer 16

It is filtered out in the spleen and presented to T cells in the spleen

Question 17

Compare the functions/properties of immature and mature dendritic cells

Answer 17

Immature: principal function is antigen capture (is constantly sampling); there is expression of Fc receptors and mannose receptors; expression of molecules involved in T cell activation is low

Mature: principal function is antigen presentation to T cells; downregulates its ability to take up antigen so it doesn’t waste energy sampling when it needs to present its antigen; high expression of molecules involved in T cell activation

Question 18

Dendritic cells vs. B cells as antigen presenting cells

Answer 18

DCs effectively deliver both signals needed to activate T cells; they are the most efficient APC to function in the primary immune response

B cells that are specific for a given Ag are rare in primary response, but dramatically expand in secondary response; they are therefore efficient as APC in the secondary

Question 19

Describe antigen uptake into endocytic components

Answer 19

Antigen is taken up from the extracellular space into intracellular vesicles → in early endosomes of neutral pH, endosomal proteases are inactive → acidification of vesicles activates proteases to degrade antigen into peptide fragments → vesicles containing peptides fuses w/ vesicles conaining MHC class II molecules

Question 20

If antigen is brought into cell by antibody (antibody mediated uptake), what happens to the antibody?

Answer 20

Antibody gets effectively recycled to cell surface while antigen goes into meet w/ MHC class II

Question 21

Describe antigen processing for exogenous (extracellular) antigens

Answer 21

Uptake of extracellular proteins into vesicular compartments of APC → processing of internalized proteins in endosomal/lysosomal vesicles

Meanwhile, MHC class II molecules synthesized in ER → has invariant chain blocking MHC binding site so antigen can’t bind yet and also transmembrane region that aids in transport → transport through Golgi → ends up in “MHC class II compartment” → endosomal enzymes destroy the invariant chain except for CLIP peptide guarding MHC groove → fuses w/ vesicle containing antigen peptide → CLIP peptide release is catalyzed by HLA-DM → allows antigen peptide to bind to MHC class II molecule → expression of peptide-MHC complexes on cell surface

Question 22

What are endogenously expressed antigens (in the cytoplasm of the cell) presented to?

Answer 22

CD8+ cytotoxic T cells

Question 23

What are endogenous antigens presented with?

Answer 23

MHC class I

Question 24

What cells are targets for CTL?

Answer 24

Any cell that expresses MHC class I can be a target for CTL

This includes antigen presenting cells and basically any nucleated cell

Question 25

Where does processing of endogenuos antigens occur?

Answer 25

In proteasome

Question 26

What are some examples of endogenous antigens?

Answer 26

Viral Tumor Self (but body won't have T cells that can respond to this self-antigen)

Question 27

What causes upregulation of proteasome components?

Answer 27

IFN (type I and II) signaling | Immunoproteasome

Question 28

What do proteasomes do?

Answer 28

``` Makes peptides of varying sizes from proteins (that have been ubiquinated and thus targeted) Some of these peptides will be appropriate for binding to MHC class I ```

Question 29

In endogenous antigen processing, how do peptides get from cytosol to where the MHC class I molecules are?

Answer 29

TAP1 and TAP2 actively take peptide and transport it across the lumen and into the ER This process requires ATP

Question 30

Describe processing of antigen in the Class I pathway

Answer 30

Production of proteins in the cytosol → proteolytic degradation of proteins by proteasome → transport of peptides from cytosol to ER by TAP → assembly of peptide-class I complexes in ER (until MHC class I molecule has peptide, don't assemble the entire molecule w/ the Beta-2 microglobulin) → transport to Golgi → Surface expression of peptide-class I complexes

Question 31

What prevents binding of Class I peptides to MHC class II in the ER (since these peptides are transported into the ER by TAP)?

Answer 31

MHC class II molecules have CLIP peptide blocking antigen binding site CLIP is only removed when MHC class II molecules have moved into the endocytic ocmpartments

Question 32

What determines the outcome of an antigen?

Answer 32

Route of entry

Question 33

Why aren't self-antigens presented by MHC molecules recognized by T cells?

Answer 33

There are either no T cells that recognize self-antigen or there is an inability to respond

Question 34

Immunodominant epitopes

Answer 34

Peptides that bind most avidly to MHC

Question 35

What is the effector function of CD4+ T cells?

Answer 35

Macrophage activation: destruction of phagocytosed antigen B cell antibody secretion: antibody binding to antigen

Question 36

Cross-presentation by dendritic cells

Answer 36

DC can effectively take up antigen from outside (such as virus infected cells) and presented to CD8+ cells

Question 37

How is cross-presentation by dendritic cells advantageous?

Answer 37

Because DC doesn't have to be infected and is therefore less susceptible to virus escape If the only way a dendritic cell could get activated was to get infected, the virus would just have to mutate so it doesn't actually infect the cells → this way, even material taken up will be presented

Question 38

Presentation of antigen by CD1

Answer 38

CD1 is a non-polymorphic MHC-like molecule that maps outside of the MHC region Like MHC class I, associates w/ beta-2 microglobulin Capable of presenting mycolic acid and lipoarabinomannan (lipid and glycolipid) from myobacteria to T cells; source of antigen is exogenous and requires processing

Question 39

What does CD1 on APC such as dendritic cells and thymic cortical cells do?

Answer 39

Able to present certain antigens (e.g. cerebrosides) to a population of CD4 T cells that express NK markers (NKT cells) or to some conventional T cells These cells make cytokines, which helps shape the immune repsonse

Question 40

What are CD1 molecules similar to?

Answer 40

MHC class I molecules Molecular structure is similar Also expresses beta-2 microglobulin

Question 41

Superantigens

Answer 41

Bind outside of the peptide-binding cleft Binds to the outside of the molecule and bring T cell receptor and MHC class II molecule together w/o processing Superantigens can turn on a lot of different cells; end up w/ a lot of cells getting activated Some bacterial toxins can thus damage the immune response

Question 42

How is antigen presentation relevant to clinical medicine?

Answer 42

``` Transplantation (organs, bone marrow, stem cells) Transfusion Cancer: can tumor antigens be presented? Infectious disease: upregulation and downregulation of MHC class I Autoimmunity Immunodeficiency Immunotherapy Vaccination ```