4: Antigen presentation

Question 1

Antigen Presenting Cells

Answer 1

• Dendritic cells, macrophages and B-cells
• They activate killer (CD8) (cross-presentation) and Th (CD4) cells.
• MHC-II and co-stimulation is increased when activated (for T-cell activation)
• Can activate the adaptive immune system
• DCs and B-cells can recognize the invader with TLRs

Question 2

Major histocompatibility complex (MHC)

Answer 2

• On the outside of cells
• Are high polymorphic: many versions of the MHC genes

All have a slightly different affinity for different peptides to increase the scope of peptides you can present

12 genes, 6 for class I (HLA-A, -B, -C) and 6 for class II (HLA-DP, -DQ, -DR)

Question 3

MHC class I

Answer 3

Are expressed on all nucleated every cell and present fragments to killer T cells (CD8); displays proteins manufactured inside the cell

Question 4

MHC class II

Answer 4

Are expressed exclusively on immune cells and present peptides to Th cells (CD4); advertises what is happening outside the cell to alert danger

Has larger and open grooves so longer peptides can be presented (also fats and carbs)

Question 5

Human Leukocyte Antigen (HLA)

Answer 5

The same as MHC

Question 6

Genes of MHC class I

Answer 6

HLA-A, -B, -C located on chromosome 6, 2 copies of chromosome 6, so a total of 6 class I MHC genes

Each class I HLA protein pairs with ß2-microglobulin to make up the complete MHC class I molecuel

Question 7

Presentation on MHC class I

Answer 7

All nucleated cells in the body presents peptides originating **inside* the cell (endogenous); large number of difference peptides fitting the amino acids present at the ends of the binding groove

Question 8

NK cells and MHC-1

Answer 8

NK cells screen for self MHC-I, not what is inside of it

Destroys the cell if cells are not presenting/or cannot bind the self-MHC-I

The balance between the signals from inhibiting (detecting MHC-I) and activating (always on) receptors in NK cells determine if the NK cell responds

Red blood cell will not get destroyed, because they don’t give off danger signals

Question 9

Killer/cytotoxic T cells (CD8) and MHC-I

Answer 9

Screen for MHC I and can recognize the non-self peptide to determine if it is invaded by a virus or parasites and should be destroyed

Destroys the cell if foreign peptides are presented by perforin, granzymes or FasL which induces apoptosis –> will be eaten

Some viruses contain genes that prevent MHC-I expression on the surface

Question 10

Explain the steps of MHC-I presentation

Answer 10

1. Proteins from the cytoplasm end up in the proteasome and cuts these proteins in peptides
2. TAP transports the peptides into the ER
3. In the ER, you have MHC-I complexes. If the peptides have the right length, they will end up in the MHC-I. Otherwise, they are transported out of the ER and degraded further.
4. The complex of the peptide and the MHC-I transports to the golgi and then to the surface out of the cell.
5. These will be recognized by CTLs if they are non-self

Question 11

Presentation on MHC class II

Answer 11

Peptides derived from the outside (exogenous) are taken up an presented by professional APCs: B-cells (later phase), DC (activates virgin T-cells) and macrophages. They also provide co-stimulation and cytokines and activate *CD4+/Th cells

Question 12

Explain the steps of MHC-II presentation

Answer 12

1. Proteins are taken up from the surrounding by phagocytosis by APCs.
2. They are cut by the low pH into small peptides.
3. MHC-II are synthesized in the ER and can’t be empty; invariant chain shields the self-peptides from the MHC-II until it reaches the phagosome
4. The MHC-II-invariant chain complex will be transported via the Golgi* to the phagosome
5. Peptides are clipped by the CLIP molecule in the right size for the groove of the MHC-II. The invariant chain is digested into CLIP; removes the invariant chain and makes sure that only high-affinity peptides end up in the MHC-II.
6. HLA-DM releases CLIP from the MHC-II complex
7. The MHC-II complex will go to the surface and display the exogenous peptide

Question 13

Invariant chain

Answer 13

Shields the endogenous peptides from the MHC-II, and guides the MHC-II out through the Golgi to endosomes in the cytoplasm.

a and ß chains making up the MHC-II molecule, are produced in the cytoplasm and injected to the ER where they can bind to an invariant chain. Is eventually digested into CLIP.

Question 14

Auto-immunity

Answer 14

Self-recognition on MHC-II by Th cell

Question 15

What three signals does a naive T cell in the lymph node need for activation?

Answer 15

1. TCR binding with MHC-II + peptide; must recognize its cognate antigen
2. Co-stimulation by APCs: protein B7 on APCs plug into CD28 on the CD4+ Th cell + ICOS
3. Cytokines: APCs make cytokines to generate the right subset of Th-cells (and CTLs) to make a tailored response

Question 16

Dendritic cell (DC)

Answer 16

• DCs can be activated by TLRs and TNF and can travel to the lymph node.
• There they can activate virgin T-cells with high levels of MHC-I and MHC-II loaded with the appropriate peptides and plenty of B7 proteins
• Process depends on the amount of damage
• Do not kill! It functions as a bridge between the innate and adaptive system

(Can also if they recognize viral structures that they migrate to T cell-area –> activates CD4 Th-cells and migrate and support B cells)

Question 17

Macrophage

Answer 17

Do not travel so much, but do kill and re-stimulate experienced/activated T-cells

Question 18

Experienced B-cells

Answer 18

Are activated and can serve as APCs. Late in the response they concentrate antigens and activate Th-cells.

BCRs have a high affinity for the antigen.

A lot of B-cells + lot of inflammation: can cluster a lot of antigen together