Antigen Capture and Presentation Flashcards
1
Q
- type of interleukin produced by APCs
- promotes the development of Th1 responses and is a powerful inducer of IFNγ production by T and NK cells
A
IL-12
2
Q
- type of interferon/cytokine
- important activator of macrophages and inducer of Class II major histocompatibility complex (MHC) molecule expression
A
IFNγ
3
Q
- a type of cytokine involved in the acute phase reaction
- produced chiefly by macrophages, but can be produced by many other cells
- able to induce fever, apoptotic cell death, cachexia, inflammation and to inhibit tumorigenesis, viral replication, and respond to sepsis via IL-1 and IL-6-producing cells
A
TNF-α
4
Q
- an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine
- mediator of fever and is an acute phase protein
- can be secreted by macrophages in response to PAMPs
- stimulates acute phase protein synthesis, and production of neutrophils in bone marrow
A
IL-6
5
Q
How does the innate immune reponse initiate adaptive immune response? (2 signals)
A
- APCs process and present antigen to T lymphocytes
- Generation of surface molecules that function as co-stimulatory signals with antigen to activate T and B lymphocytes
6
Q
What are antigens in the periphery filtered by?
A
lymph and lymphoid tissues
7
Q
What are antigens in the blood filtered by?
A
spleen
8
Q
How are antigens processed? (2 steps)
A
- phagocytosed or pinocytosed by APCs
- APCs convert proteins to peptides for display
9
Q
What are the 3 main types of APCs?
A
- dendritic cells
- macrophages
- B lymphocytes
(other cells than express MHC II can act as APCs in certain cases, i.e. thymic epithelial cells)
10
Q
- type of APC, level of MHC class II: very high
- level of constitutive co-stimulatory molecule expression: high
- capable of cross presentation: +++
- activates naive T cells: yes
- activates effect and memory T cells: yes
A
dendritic cells
11
Q
- type of APC, level of MHC class II: high
- level of constitutive co-stimulatory molecule expression: moderate
- capable of cross presentation: ++
- activates naive T cells: no
- activates effect and memory T cells: yes
A
macrophages
12
Q
- type of APC, level of MHC class II: high
- level of constitutive co-stimulatory molecule expression: low
- capable of cross presentation: +/-
- activates naive T cells: no
- activates effect and memory T cells: yes
A
B cells
13
Q
__ ____ can only recognize antigens in the form of being presented by APCs
A
T cells
14
Q
________ and __ ____ can recognize free peptide antigens
A
macrophages, B cells
15
Q
_______ ____ are the only cells that can activate naive T cells
A
dendritic cells
16
Q
- type of antigen presenting cell
- high constitutive expression of MHC/HLA II expression and co-stimulatory molecules
- activate mature, naive T cells (present to them in peripheral lymphoid tissue)
- present in all tissue
- major cytokines produced: TNF, IL-6, IL-12, and IL23
A
dendritic cells
17
Q
- type of antigen presenting cell
- present in blood and tissues
- promote innate anti-viral state
- release type I interferons
A
plasmacytoid dendritic cells
18
Q
What happens when dendritic cells are activated by an antigen?
A
- lose adhesive markers, up-regulate CCR7 (lymphatic endothelium), increase expression of MHC and CD80 (B7)
- travel to regional lymphoid tissue (mature as they migrate, process Ag to T cells)
19
Q
Why do dendritic cells lose their characteristic arrays of actin filament once they mature?
A
The actin filament is there to pull in cells/microbial particles for analysis, once they have an antigen and are matured, they lose the actin filament to travel to secondary lymphoid tissue
20
Q
Why are all cells technically able to present Ags to CD8+ T cells?
A
Because CD8+ T cells recognize antigens within MHC I, which is expressed on all nucleated cells
21
Q
- differences in these molecules (on cell surface) expressed by an individual will influence the repertoire of antigens to which T cells can respond
- function as antigen-presenting structures to T cells
- T cells cannot recognize antigens in free or soluble forms
A
HLA
22
Q
What chromosome are MHC/HLA genes located? How many MHC classes are there?
A
- chromosome 6
- 3 MHC classes
23
Q
- the total set of MHC/HLA alleles that are present on each chromosome
- encode proteins to distinguish between, self, non-self, and respond to outside threats
- most humans are heterozygous (1 from mom and 1 from dad)
- both are expressed simultaneously (co-dominant)
A
MHC/HLA haplotype
24
Q
Why is beneficial to human health that MHC/HLA haplotypes are expressed in co-dominant expression?
A
It increases the number of peptides a person can respond to = more pathogens/microbes a person can respond to
25
Why are MHC I genes more diverse than MHC II genes?
Immune system is able to detect more "self-antigens" thus it prevents auto-immunity
26
Why do epidemics generally favor those with more rare allotypes?
Because the people with more common allotypes will inherently exist more within the population, large population of allotypes = more people with those allotypes infected
Also, the disease will likely favor infection of people with those alloptypes (maybe their immune system lacks the ability to detect the pathogen vs. people with the rare allotype may have recognition of it)
27
What are the 2 main cell types that MHC/HLA I present antigens to?
1. **cytotoxic T lymphocytes (CTLs)**: either secondary recognition with help from DCs, or binding with the cell directly; induce apoptosis of cell and release IFN-γ to signal macrophages for phagocytosis and clean up of debris
2. **NK cells**: recognize infected/damaged host cell and induce apoptosis; macrophages release IL-12 which is a potent inducer of IFN-γ in NK cells, IFN-γ signals more macrophages to come to area of infection (essentially ensures the debris that is created by NK killing is cleaned up by macrophages)
\***NK cells** have a **backup system** that ensure they will not attack host cells: **MICA** and **MICB** are "kill me" signals released by host cells that are recognized by NK cell receptors (**KAR**). The KAR downstream effects are inhibited by **normal** host cell **MHC-I binding** with NK cell's **KIR**. If either of these **binding complexes** are **out of balance**, this will **activate NK cell killing**
**(CELLS HAVE TO BE INFECTED OR DAMAGED FOR EITHER OF THESE CELL TYPES TO RECOGNIZE, AKA VIRAL/ENDOGENOUS)**
28
What is the MHC/HLA I strcture?
heterodimer of two proteins
- **α chain**: encoded by MHC/HLA locus (chrom 6), forms 3 globular proteins (α1, α2, α3) where the **peptide binds** between **cleft α1** and **α2**
- **β-microglobulin**: non MHC/HLA encoded (chrom 15), associates non-covalently w/ α3, provides **structural support**
29
- area between α1 and α2 domains on MHC/HLA I
- site coded for by polymorphisms unique for each allele
- binding peptides are 8-10 AAs in length
**- each allele of MHC/HLA I has a different range of peptides than can bind in groove**
- binding depends on **conformational 3D shape** and **charge of AAs**
MHC/HLA I peptide binding cleft
30
How is MHC/HLA I synthesized? (3 steps)
1. α chains are translated in the ER (chaperone proteins hold structure in place prior to interaction w/ β microglobulin)
2. newly syn α chains associate w/ peptides from cytosolic proteins and with β microglobulin
3. complete complex is transported to cell surface
31
- encoded by HLA-D region
- 3 sets of genes for the α and β chains (DP, DQ, DR)
- primarily expressed on professional APCs (DCs, macrophages, B cells, and special case of thymic epithelial cells)
- presents antigen to CD4+ T-lymphocytes
MHC/HLA II
32
What is the structure of MHC/HLA II?
- α and β chain with four globular proteins, strong association but not covalently bonded
- each allele has a different range of peptides that can bind in the groove
- all alleles are expressed (6 α and 6 β chain, 3 from each parent)
- any α can associate with any β
33
- formed by α1 and β1 globular domains
- coding region for these domains have the great polymorphism
- 3D conformation (shape) and charge dictate peptide binding (peptides between 13-18 AAs)
- open ends allow larger peptides = greater range of peptides
MHC/HLA II peptide binding cleft
34
Why does the HLA-peptide ineraction have a slow on and off rate?
this allows the peptide-HLA complexes to persist long enough to interact w/ T cells
35
Why are T cells restricted to specific MHC types? What are the restirictions and what is this rule called?
- T cells are restricted due to binding abilities
- CD8+ T lymphocytes can only bind with MHC I, CD4+ T lymphocytes can only bind with MHC II
- this is called the rule of 8ths: CD8 X MHCI = 8 ; CD4 X MHCII = 8
36
What type of micro antigens activate CD4+ T cells? Why?
- **extracellular bacteria, parasites, toxins**
- because these do not infect cells directly, they are extracellular, thus the only way to get to their antigens is for them to be phagocytosed by APCs, which then present the antigen in **MHC II**, which is recognized by CD4+ T cells
37
What type of micro antigens activate CD8+ T cells? Why?
- intracellular bacteria, viruses, tumors
- because these microbes/tumors affect the cell internally, by either infecting or damaging the cell, causing the cell to either stop producing their own MHC I peptides, or start producing micro peptides and displaying it in **MHC I**, which alerts CD8+ T cells that something is wrong
38
How are antigens loaded in MHC/HLA I? (6 steps)
1. viruses enter cytoplasm or phagosomes
2. viral proteins synthesized and targeted for degradation by ubiquitin
3. proteasomes in cytoplasm degrades proteins into peptides
4. TAP transports peptides from cytosol to ER
5. peptide is trimmed and loaded into MHC I molecule
6. peptide-MHC I complex is expressed on surface for recognition by CD8+ T cell
39
How are antigens loaded in MHC/HLA II?
1. extracellular pathogen is taken up into endocytic vesicle
2. pathogenic antigens are processed in endosomal/lysosomal vesicles
3. MHC II are synthesized in ER and transported to endosomes via exocytic vesicles
4. pathogenic peptides and MHC II meet in vesicles where they are processed
5. the peptide-MHC II complex is brought to surface where it is recognized by CD4+ T cells
40
What is the role of Ii in antigen loading of MHC II?
Ii occupies the peptide binding cleft of MHC II so that "self antigens" don't get in there and elicit and auto-immune response
The Ii is eventually degraded to CLIP by lysosomal enzymes
(CLIP: class II invariant chain peptide)
41
What is the role of HLA-DM in antigen loading of MHC II?
it acts as a peptide exchanger, once the MHC II is ready to be brought to cell surface, HLA-DM will remove CLIP (place holder) and insert the pathogenic peptide
42
- occurs when dendritic cells ingest virally infected or transformed cells and display viral Ag to CTLs via MHC I (usually used to display self antigens)
- dendritic cells can also display the viral antigen to T helper cells (because they also have MHC II)
cross-presentation or co-stimulation
43
What is the outcome of CD4+ helper T cell activation by APCs?
- macrophage activation (phagocytosis)
- B cell activation (antibody production)
44
What is the outcome of CD8+ cytotoxic T cell activation by MHC I?
killing of antigen expressing target cell
45
- caused by defects leading to deficiency in HLA class I or II expression
- HLA I: decreased cytotoxic T cell responses, poor response to viruses (intracellular), chronic respiratory infections
- HLA II: reduced T helper cell due to failed thymic selection, reduced antigen presentation to mature CD4+ T cells, decreased humoral and cell mediated responses; severe, recurrent infections; rare to see because people with this usually die early on in life
bare lymphocyte syndrome
46
MHC/HLA summary
