Adaptive Immunity T Cells 2

Question 1

Summarise antigen processing to display it on a cell

Answer 1

T cell expressing alpha and beta T cell receptor will recognise peptides which are complexed with MHC molecules.

Antigenic peptides presented by MHC Class 2 are derived from intracellular pathogens that release proteins to the cytosol (recognised by CTLs).

Antigenic peptides presented by MHC 2 are derived from proteins of extracellular pathogens that are endocytosed by antigen presenting cells (recognised by Th cells).

• Antigen processing breaks down proteins to peptide which may be bound by MHC molecules exported to the cell surface.
• The processing part associated with MHC 1 and MHC 2 are different in separate cellular compartments.

Question 2

Explain how the MHC 1 antigen processing pathway occurs

Answer 2

(All cells in the body express MHC 1 so can be targets for cytotoxic T cells if they are infected).

Proteins in the cytosol are broken down into peptides by proteosomes.
The peptides are transported by the endoplasmic reticulum by the TAP (transported associated with antigen processing) transporter.
Here, some of the peptides might be newly synthesised MHC class 1 proteins and the peptide MHC complex is transported to the cell surface in vesicles.

At the cell surface, the peptide MHC complex is recognised by CD8 expressing CTL to recognise the antigen is pathogenic to kill the infected cell.

This pathway cannot tell between proteins from pathogens and self proteins as expressing proteins on the cell surface is a normal process for a cell. CD8 T cells will not recognise the self proteins.

Question 3

Summarise the MCH 2 antigen processing pathway

Answer 3

(only occurs in cells that are associated with Th cells)

Antigens processed by the class 2 pathway are derived from the extracellular environment and are endocytosed in membrane vesicles.

Dendritic cells and macrophages are important in sampling the extracellular environment to detect pathogens. These cells migrate extensively around the body.

The endocytic vesicles fuse with lysosomes contain cellular proteases to break the protein down (slightly longer than MHC 1 pathway).

The endolysosome vesicles fuse with membrane vesicles which contain newly synthesised MCH 2 proteins. The class 2 proteins are synthesised with a protein called the invariant chain. This blocks the antigen binding site of the MHC 2 molecules so they cannot be occupied by peptides from the intracellular proteins.

When class 2 vesicle fused with the endolysosome vesicle, proteases digest the invariant chain so that the peptide binding site becomes available to bind to peptides derived from extracellular proteins.
The MHC 2 complex and extracellular peptides are transported to the surface of the APC where they may be recognised by antigen specific T helper cells.

Question 4

Why is the MHC peptide binding highly promiscuous?

Answer 4

There are only a few residues in peptide that are critical for binding.
MCH 1 binds peptides of 8-10 residues, only 1/2 contribute to binding.
MHC 2 binds peptides of 12-17 residues, only 2/3 contribute to binding.
All other position can vary so a large number of peptides can bind to any MHC molecule.

Question 5

How do T cells recognise other antigenic molecules which are not antigens?

Answer 5

• the gamma delta receptor T cells do this
• derived from separate gene loci with fewer V gene segments
• reflect reduced diversity of TCR specificity
• they can recognise bacterial-derived metabolites or lipids associated with MHC 1 surface receptors
• these antigens don’t require processing and are displayed on the target cell bound to MHC class 1 like molecules.

Question 6

Why do APCs express both MHC 1 and MHC 2 proteina?

Answer 6

So they can bind to and activate both CD4 Th cells and CD8 CTLs.

Question 7

Why does T cell actiavation occur in the lymph node?

Answer 7

T cells are exposed to many APC to increase the likelihood that they will encounter those that display the cognate antigen for the particular T cell

Question 8

What are the 3 cell signals required for T helper cell activation?

Answer 8

1. The first signal is provided by the APC is a result of T cell receptor engagement with the MHC 2 complex. When the TCR binds to antigen MHC, CD4 binds to the MHC 2 protein component and activates a protein kinase in the T cell that phosphorylates CD3. This then recruits further kinases that transmit the first activating signal to the T cell.
2. Further signalling is provided by either 2 related molecules, CD80 or CD86, on the APC binding to CD28 on the T cell surface. These two signals stimulate interleukin 2 production which acts in an autocrine manner to further activate the T cell.
3. The third signal from the APC is in the form of cytokines to stimulate T cells proliferation and differentiation into memory and effector cells. This signal determines the type of immune response.

Question 9

How do cytotoxic T cells get activated?

Answer 9

1. This cell has its receptor is associated with CD8 which binds to MHC 1 molecules. The TCR binds both to MCH 1 and the antigenic peptide.
   CD8 induces phosphorylation of CD3, leading to further signalling to the cytotoxic T cell.
2. Further signalling is provided by either 2 related molecules, CD80 or CD86, on the APC binding to CD28 on the T cell surface. These two signals stimulate interleukin 2 production which acts in an autocrine manner to further activate the T cell.
3. Further activation requires T helper cells (particularly if they have been activated by the same APC simultaneously). Th cells secrete interleukin 2 which is needed for CTL proliferation.
   Th cell also induces expression by the antigen presenting cell and further co-stimulatory ligands such as CD40 binding to CD154 on the CTL which is a 4th activation signal.

Once activated the Tc cell proliferates giving rise to effector and memory cells.

Question 10

Fill in gaps:

Interactions of microbial —- with innate immune receptors of —- cells results in secretion of —- that determine the nature of the immune response.

Answer 10

• antigens
• dendritic
• cytokines

Question 11

What are the 3 main cells that secrete cytokines?

Answer 11

1. TH1 for targeting intracellular viruses.
2. Th2 for extracellular parasites
3. Th17 for extracellular bacteria and fungi.

Question 12

How do we switch off the immune system?

Answer 12

T cells change from expressing co-stimulatory molecules (CD8 and CD4) and replace with inhibitory receptors which don’t activate target cells.
T cells may express receptors for mediators which may induce apoptosis.