CSIM 1.24 T-Cells 2

Question 1

Describe the maturation of T cells in the thymus

Answer 1

• T cells arrive as a ‘double negative cells’ (no markers which show that it is a T cell)
  
  • These progresses through stages of DN1 to DN4 as they begin to mature in the subcapsular region, as recombination of TCRs is occurring.
  • As this maturation occurs, the DN T-cells migrate through the cortex towards the medulla
  • Most of the time this recombination does not produce a functional TCR (because it cannot bind to MHC, and the cell apoptoses
  • Positive selection occurs of cells with TCR which can bind to MHC
  • These develop into ‘immature double-POSITIVE thymocytes’ by expressing both CD4 AND CD8
  • These double-positive cells receive a different maturation signal to lose either CD4 or CD8 depending on which MHC class they bind to.
  • These T-cells then migrate into the medulla and negative selection occurs at the medullary epithelial cells
  • The mature T cells are then released as CD4+8- or CD8+4-

Question 2

If thymic maturation occurs in early life, what is its function

Answer 2

To act as a school for T cells to mature and randomly generate TCRs for any antigen which may be encountered in later life.

To prevent autoimmunity by killing T cells specific for human antigens

Question 3

Name the two processes which determine which T cells survive in the thymus. Briefly describe what each does and what the end result is

Answer 3

Positive selection
• The TCR is tested to ensure it recognises the MHC molecule

Negative selection
• Expresses lots of tissue self-antigen
• Looks for TCRs which bind to this self-antigen which may cause autoimmunity and causes deletion of this cell

These two processes lead to cells which recognise MHC but do not bind to self-antigens

Question 4

How does autoimmunity still occur?

Answer 4

Negative selection only works when T cell receptors strongly bind to self-antigen, therefore TCRs which only lightly bind to self-antigen may still be released and become a proponent of autoimmunity

Question 5

How does the thymus determine whether a T cell will mature into CD4+8- or CD8+4-?

Answer 5

If the transgenic TCR recognises MHC I in the thymic epithelial cells, then CD8+4- T-cytotoxic cells are generated

If the transgenic TCR recognises MHC II in the thymic epithelial cells, then CD4+8- T-helper cells are generated

Question 6

Describe what is meant by MHC restriction

Answer 6

A T-cell will only react if the class of MHC molecule antigen is presented on is the same class the T-cell bound to in the thymus

The MHC is required for this, and ‘free’ antigen will not trigger any kind of response

Question 7

How might self-antigens be made available for an adaptive immune response?

Answer 7

Dead cell fragments are cleaned up by macrophages. These have the potential to present antigens from these dead self-cells to T cells in the lymph nodes.

Question 8

Why do cells that apoptose naturally never trigger an autoimmune response?

Answer 8

Naturally-apoptosing cells do not instigate an inflammatory response, therefore no cytokines are released to stimulate the macrophage to present the antigens

Question 9

Describe antigen presentation of cytosolic pathogens

Answer 9

• A cytosolic pathogen (i.e. virus) invades a cell.
  
  • Some of this virus will come across a proteosome (by chance)
  • The proteosome will break up the protein into a peptide antigen
  • This peptide antigen is transported by TAP1 and TAP2 to the endoplasmic reticulum
  • MHC I is being synthesised in the ER lumen
  • MHC I binds to the TAP protein with the associated antigen
  • This peptide binds to MHC I which is transported to the surface of that cell
  • This is recognised by T-cytosolic cells containing CD8
  • The T-cytosolic cell stimulates the cell to apoptose

Question 10

How can some cytosolic pathogens evade antigen presentation to MHC I?

Answer 10

They may replicate in endosomes

Question 11

How are pathogens in endosomes made available to MHC II molecules in macrophages and dendritic cells?

Answer 11

• The pathogen is phagocytosed into an endosome.
  
  • This endosome is acidified, which breaks down the proteins of the pathogen inside
  • This endosome merges with a an ER vesicle containing MHC II and a protein called ‘invariant chain’ (Li) - (IMG 61)
  • Li usually blocks the cleft of MHC II, but due to the acid from the endosome it breaks down, revealing the cleft
  • The cleft is now open for antigens from the broken down pathogen to bind
  • The MHC II vesicle moves to the plasma membrane and waits for a T-helper cell with CD4

Question 12

What is toxic shock? (not septic shock)

Answer 12

Caused by the activation of many lymphocytes causing massive cytokine release
• 20% of T cell population activated (instead of around 1% in most infections)
• Causes erythema
• Also causes the features found in septic shock

Question 13

What is the criteria for activation, differentiation and proliferation of T cells?

Answer 13

Antigen (complimentary to the specific TCR) in association with MHC I or II presented by APCs

ALSO needs co-stimulatory signal presented by dendritic cells, macrophages (and B cells). This must be the same cell which is presenting the antigen. These signals can be:
• B7.1 (a.k.a. CD80)
• B7.2 (a.k.a. CD86)
These bind to a receptor called CD28 on the surface of T cells

Cytokines from the APC stimulate the cytokine receptors (IMG 58),

All three receptors (TCR, CD28, cytokine) modulate genes in order to bring about activation, survival and differentiation (IMG 62)

Question 14

What happens if a T cell is activated by an antigen+MHC but does not receive any co-stimulatory signal?

Answer 14

‘Anergy’ of the T cell occurs, and will not respond again to its antigen

Question 15

After activation, what is needed for a T cell to begin respond?

Answer 15

Once a T cell has been stimulated once (with the three components necessary), in the future it will only ever need the first signal (MHC + antigen) to respond

(i.e. ‘memory’ T cells)