L7: Antigen Processing and Presentation Flashcards
How do B cells “see” antigen?
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)
How to T cells “see” antigen?
Recognize protein antigens as discrete peptides
Recognize linear epitopes (don’t recognize non-contiguous epitopes)
Recognize antigen only when it is bound to MHC
How do CD8+ cytotoxic cells “see” antigen? How do they respond?
“See” antigen complexed to MHC class I and respond by killing the infected cell
How do CD4+ helper cells “see” antigen? How do they respond?
“See” antigen complexed to MHC class II and respond by proliferation and production of cytokines
What must APCs express in order for T cell to recognize and respond to a foreign peptide antigen?
APC must express MHC molecules that are recognized as self
What are “self” MHC?
Those MHC antigens that the T cell encountered during development in the thymus
What are cytosolic pathogens presented to?
Presented to effector CD8 T cells
Effect is cell death
What are intravesicular pathogens presented to?
Presented to effector CD4 T cells
Effect is activation to kill intravesicular bacteria and parasites
What are extracellular pathogens and toxins presented to?
Presented to effector CD4 T cells
Effect is activation of B cells to secrete Ig to eliminate extracellular bacteria/toxins
What recognizes exogenous antigens?
CD4 cells
These antigens are processed and presented w/ MHC class II
The CD4+ T cells respond with proliferation and cytokine production
What are the professional antigen presenting cells? What do they do?
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
What is the response of dendritic cell antigen uptake?
Naive T cell activation: clonal expansion and differentiation into effector T cells
What is the response of macrophage antigen uptake?
Effector T cell activation: activation of macrophages (cell-mediated immunity)
What is the response of B cell antigen uptake?
Effector T cell activation: B cell activation and antibody production (humoral immunity)
Where are dendritic cells found?
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
What occurs if antigen enters blood stream?
It is filtered out in the spleen and presented to T cells in the spleen
Compare the functions/properties of immature and mature dendritic cells
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
Dendritic cells vs. B cells as antigen presenting cells
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
Describe antigen uptake into endocytic components
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
If antigen is brought into cell by antibody (antibody mediated uptake), what happens to the antibody?
Antibody gets effectively recycled to cell surface while antigen goes into meet w/ MHC class II
Describe antigen processing for exogenous (extracellular) antigens
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
What are endogenously expressed antigens (in the cytoplasm of the cell) presented to?
CD8+ cytotoxic T cells
What are endogenous antigens presented with?
MHC class I
What cells are targets for CTL?
Any cell that expresses MHC class I can be a target for CTL
This includes antigen presenting cells and basically any nucleated cell
Where does processing of endogenuos antigens occur?
In proteasome
What are some examples of endogenous antigens?
Viral
Tumor
Self (but body won’t have T cells that can respond to this self-antigen)
What causes upregulation of proteasome components?
IFN (type I and II) signaling
Immunoproteasome
What do proteasomes do?
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
In endogenous antigen processing, how do peptides get from cytosol to where the MHC class I molecules are?
TAP1 and TAP2 actively take peptide and transport it across the lumen and into the ER
This process requires ATP
Describe processing of antigen in the Class I pathway
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
What prevents binding of Class I peptides to MHC class II in the ER (since these peptides are transported into the ER by TAP)?
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
What determines the outcome of an antigen?
Route of entry
Why aren’t self-antigens presented by MHC molecules recognized by T cells?
There are either no T cells that recognize self-antigen or there is an inability to respond
Immunodominant epitopes
Peptides that bind most avidly to MHC
What is the effector function of CD4+ T cells?
Macrophage activation: destruction of phagocytosed antigen
B cell antibody secretion: antibody binding to antigen
Cross-presentation by dendritic cells
DC can effectively take up antigen from outside (such as virus infected cells) and presented to CD8+ cells
How is cross-presentation by dendritic cells advantageous?
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
Presentation of antigen by CD1
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
What does CD1 on APC such as dendritic cells and thymic cortical cells do?
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
What are CD1 molecules similar to?
MHC class I molecules
Molecular structure is similar
Also expresses beta-2 microglobulin
Superantigens
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
How is antigen presentation relevant to clinical medicine?
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
