T Cell Structure and Signalling

Question 1

T cell development occurs in the BLANK

Answer 1

T cell development occurs in the thymus

Question 2

T cell differentiation occurs in the BLANK

Answer 2

T cell differentiation occurs in the periphery

Question 3

What do T cells do?

Answer 3

T cells respond to bacterial, viral or tumour antigens
and mount an immune response to clear the bacteria, virus or tumour from the body.

T cell function in response to pathogens is shaped by antigen, pro-inflammatory cytokines, inhibitory receptors and environmental stimuli (e.g. oxygen, AA, glucose, iron availability).

T cells do not respond to soluble bacteria or viral antigens but are triggered by peptides presented to them by major histocompatibility (MHC)
molecules on the surface of other cells.

Question 4

T cell differentiation:

Answer 4

Naive -> TCR Activated -> Effector -> Memory

Naive:
Metabolically inactive
Not proliferating - G0
Negligible protein synthesis
No nutrient and AA transport

TCR Activated:
Metabolically active
G1/S phase of cell
cycle
Increased protein
synthesis
Active nutrient and AA
transport

Effector:
Metabolically active
Rapidly proliferating
Active nutrient and AA transport
High rates of protein synthesis
Producing effector molecules 

Memory:
a small proportion of long
lived T cells will persist after
encountering a pathogen. These cells
can respond very quickly to the same
antigen again.

Question 5

MHCs

Answer 5

Most cells in the body express MHC Class I molecules
MHC class II molecules are present on specialised antigen presenting cells (APCs) e.g. Dendritic cells, activated macrophages, activated B cells.

These are loaded with either self or foreign peptides

MHC/self peptide complexes trigger T cell survival
MHC/pathogenic peptides presented on the surface of specialised APCs induce T cell immune responses

Question 6

TCR structure:

Answer 6

CD4/8 chains (alpha/beta, gamma/delta)
CD3 Chains (gamma/delta/epsilon/zeta)
ITAM domains (Immune Tyrosine based Activation Motif)
Variable region
Constant region
Cytoplasmic tails
Transmembrane Tails

KNOW HOW TO DRAW

Question 7

T Cell Receptor (TCR):

Answer 7

T cells will not respond to peptide alone, they need peptide presented to them.
The key receptor that controls the responses of T lymphocytes is the T Cell Receptor.

The TCR is a multisubunit complex expressed on the
surface membrane of all T cells
T cells can be subdivided into two major subpopulations
based on the type of T cell receptor they express.

Question 8

T cells can be subdivided into two major subpopulations

based on the type of T cell receptor they express:

Answer 8

alpha/beta T cell receptor (because it uses an alpha/beta dimer to recognise antigen)
- Expressed by majority of recirculating T cells
in the blood and lymphatic system
- recognise small peptides in complexes with MHC class I or class II molecules
- primarily responsible for antigen-specific
cellular immunity
- The ligand for the alpha/beta TCR is peptide/MHC complexes

gamma/delta T cell receptor (because it uses an gamma/delta dimer to recognise antigen)

• Expressed by majority of T cells lining the gut and in the skin
• not MHC restricted
• involved in specific primary immune responses, particularly in young animals, tumour surveillance, and have been implicated in wound healing.
• γδ TCR ligands can be small bacterial phosphoantigens etc.

Question 9

T cells in the blood and lymphatics that express alpha/beta TCRs can be subdivided into two major subgroups based on the type of coreceptor for MHC that they express:

Answer 9

CD8 T Cell:
- Produce effector molecules including granzymes, tumor necrosis factor and perforin 
- kill pathogen infected
cells and tumor cells.
- The CD8 molecule is a coreceptor
for MHC class I molecules so these
cells are triggered by peptide/MHC
class I expressing cells.

CD4 T Cell:
- Secrete cytokines including
interferon gamma
- induce the activation of other immune cells including macrophages.
- The CD4 molecule is a coreceptor
for MHC class II molecules so these cells are triggered by peptide/MHC class II expressing cells

Normal ratio of CD4:CD8 T cells in blood is 2:1

Question 10

How do T cells recognise a wide range of different antigens?

Answer 10

Each T cell can express a unique antigen receptor
This is because the alpha/beta or gamma/delta subunits, which are the receptor subunits that recognise peptide/MHC complexes, are highly variable proteins.

The other antigen receptor subunits (CD3 gamma/delta/epsilon/zeta) are invariant.
They do not recognise antigen but are needed for signal transduction to transmit signal transduction

Question 11

Why are alpha/beta/gamma/delta subunits highly variable?

Answer 11

Because the genes that encode these proteins undergo gene rearrangements.
Random rearrangements of the exons is controlled by recombinase genes (Rag1/2).
Occurs during T cell development.
Called VDJ Recombination.

Question 12

TCRs have no intrinsic catalytic activity

TRUE OR FALSE

Answer 12

TRUE
The TCR has no intrinsic catalytic activity but is coupled via signaling motifs known as ITAMs to cytosolic tyrosine kinases Lck/fyn and ZAP70.

Triggering the TCR activates these
tyrosine kinases.

Question 13

T cell responses to immune stimulation:

Answer 13

1. Change migration pattern and move to site of infection
2. Proliferate and clonally expand
3. Induce expression of genes for cytokines, cytokine receptors etc
4. Upregulate growth and protein synthesis to permit rapid cell
   division and cytokine production.
5. Differentiate into killer cells or different types of helper T cells to
   make sure the immune response is appropriate

Question 14

T cell heterogeneity after activation:

Answer 14

CD4+:

• Regulatory T Cells
• Th1
• Th2
• Th17
• Memory T Cells

CD8+:

• Memory T Cells
• CTLs

Question 15

How can antigen activated T cells differentiate to make different types of effector cells?

Answer 15

Controlled by signaling pathways induced by cytokines produced by activated T cells or cells of the innate immune system.

The type of cytokine produced depends on the pathogen.

Therefore Type of T effector cell produced is dependent on cytokine signalling which is determined by the pathogen.