Adaptive immune system - T cells

Question 1

What cells do the myeloid and lymphoid progenitor give rise to?

Answer 1

Question 2

Describe the lymphoid progenitor cell.

Answer 2

• It gives rise to lymphocytes.
• It comprise of 20-30% of the peripheral WBCs.
• They are 6-10um in diameter with a large nucleus and a small halo of cytoplasm.
• Upon activation by antigens, they become effector cells or memory cells.
• There are two main types: T-cells and B-cells (T-lymphocytes and B-lymphocytes).
• In the early developmental stage, cells can either pass to the thymus (and become T-cells) or stay in the bone marrow (and become B-cells).

Question 3

Describe the role of the thymus in T-cell development.

Answer 3

• T-cells mature in the thymus.
• Immature T-cells develop in the bone marrow then migrate to the thymus to encounter self-antigens.
• During this process, many T-cells die by apoptosis, leaving just those that can generate a useful response to infection.
• The thymus enlarges during childhood, then atrophies (decreases in size) at puberty.

Question 4

List and describe the four T-cell subsets.

Answer 4

1. αβ T-cells (helper T-cells) (express CD4 and CD3):

• Activated to secrete cytokines to help immune responses, or become memory cells.
• 2 main subgroups: TH1 and TH2 (also Th17).

1. Cytotoxic T-cells (express CD8 and CD3):

• Activated to kill infected targets, or to become memory cells.
• Usually cytotoxic in nature and kill via the release of the toxic contents of granules, or induction of apoptosis.

1. Regulatory T-cells:

• Mainly CD4+ (some CD8+) cells able to affect immune responses by either suppressing them or activating them through direct cell contact or by the secretion of soluble factors (cytokines).
• 2 types: natural or inducible.

1. ​γδ T-cells:
   * T-cell receptor (TCR) formed of the γδ chain recognise lipid antigens.

Question 5

Describe the T-cell receptor (TCR).

Answer 5

• It is a dimeric molecule made up of either αβ or γδ chains linked by disulphide links (S-S).
• Each chain has a variable and a constant Ig like domain.
• The variable region has hypervariable regions which are antigen binding sites.
• It’s associated with the signalling complex CD3 (CD3 is the identifier of the T-cell).

Question 6

Alpha beta VS gamma delta

Answer 6

Question 7

Describe the Major Histocompatibility Complex (MHC).

Answer 7

• It’s present on T-cells; it’s a surface-expressed molecule which binds peptides derived from antigens.
• MHC encodes for human leukocyte antigens (HLA).
• There are two types of MHCs:
  
  • MHC Class I (HLA-A,B and C), expressed on all nucleated cells.
  • MHC Class II (HLA-D), expressed on ‘professional’ antigen-presenting cells (dendritic cells and macrophages).
• MHC I is made of an α chain and β2-microglobulin; it is recognised by CD8+ T cells.
• MHC II is made of an α chain and β chain; it is recognised by CD4+ T cells .

Question 8

What are the steps for antigen processing and presentation to CD4 cells?

Answer 8

1. There is uptake of the pathogens antigen into a vesicle of an antigen presenting cell. The vesicle fuses with a lysosome.
2. Within the vesicle the protein is broken down into small peptides.
3. At the same time a MHC molecue is generated in the ER.
4. A chaperon is a moolecule that makes sure something gets to the right place.
5. In order to stop the MHC molecule from binding a peptide in the wroing place, it binds a particular molecule called invariant chain (li) into the binding cleft if the molecule. (So nothing can bind to the molecule if the invariant chain is bound to it).
6. The invariant chain bound class II molecule then forms a exoctyic vesicle which fuses with a lysosome and will allow the peptide to bind to the MHC class II molecule.
7. To do this a molecule called HLA - DM takes away the CLIP (class II associated invariant peptide) part of the invariant chain.
8. This allows a peptide to bind to the MHC class II molecule.
9. The peptide-MHC complex is presented on the surface of the cell allowing a CD4+ helper T cell to recognise it.

Question 9

What are the steps for antigen processing and presentation to CD8 cells?

Answer 9

1. If there is a virus in the cytoplasm the cell will coat the virus in protein called ubiquitin.
2. This targets it to be degraded by a proteasome, which chops up the viral protein into peptides which enter into the cytosol.
3. The peptides get transported into the ER and get chopped up to even smaller pieces, where they fit the shape of the groove in the MHC I molecule.
4. The MHC I – viral peptide molecule is then transported to the membrane and presented on the surface where it can be recognized by CD8+ T cells.

Question 10

List some antigen-presenting cells.

Answer 10

1. dendritic cells
2. tissue specific dendritic cells
3. macrophages
4. B-cells
5. endothelial cells under some conditions

Question 11

What happens to T-cells in the thymus?

Answer 11

• T-cells in the thymus enter as thymocytes, not expressing either CD4 nor CD8 (double negative), go through a stage of expressing both (double positive), followed by a decision to be either CD4+ or CD8+.
• They are positively selected to bind to molecules called MHC, and negatively selected if they bind self-peptides (‘education’).

Question 12

Describe CD4 T cells.

Answer 12

• They recognise a peptide in the binding groove of MHCII.
• T helped cells: produce a cytokine profile which directs the immune response to a certain outcome.
• T-regulatory cells: responsible for ending an immune response.

Question 13

Describe CD4+ Th1 cells.

Answer 13

• They express the co-receptor CD4.
• They help to activate the cellular immune response (it activates macrophages and cytotoxic T-cells).
• It produces the γ-interferon.
• Th1 responses are effective against intracellular infections, bacterial, protozoal and viral.
• Th1 and Th2 are mutually antagonistic.

Question 14

Describe CD4+ Th2 cells.

Answer 14

• They express the co-receptor CD4.
• They help to activate the humoural immune response.
• They produce interleukin 4, 5 and 13.
• They activate B-cells to produce antibodies.
• Th2 responses are effective against extracellular cellular infections, bacterial, protozoal and viral.
• They’re effective in IgE production against helminth (worm) infections.
• Th1 and Th2 are mutually antagonistic.

Question 15

Describe CD4+ Th17 cells.

Answer 15

• It expresses the co-receptor CD4.
• They help to protect gut mucosa.
• They produce interleukin 17 and 22.
• It recruits neutrophils to sites of infection.
• Th17 responses are effective against extracellular bacteria and fungi.
• It’s effective in promoting neutrophil-mediated inflammation and helping Th1 cells to induce phagocytosis and subsequent killing of pathogens.

Question 16

Describe CD4+ Treg cells.

Answer 16

• They express the co-receptor CD4, CD25 and FoxP3.
• They maintain immune tolerance and suppress immune responses.
• They produce anti-inflammatory cytokines IL10 and TGFβ.
• They also have a contact-dependant immunosuppressive effect.
• Tregs inhibit the effector functions of CD4+ and CD8+ T-cells.
• Also, they inhibit the antigen presentation function of B-cells and other antigen-presenting cells.

Question 17

Describe CD8+ cytotoxic T-cells (CTL).

Answer 17

• They express the co-receptor CD8.
• They eliminate intracellular functions.
• They produce IL2, TNFα and γIFN.
• They also have a role in anti-tumour immunity and rejection of transplants.
• They kill infected cells in an antigen-specific and cell-contact dependent manner.

Question 18

How does the CD8+ cytotoxic T-cells killing mechanism occur?

Answer 18

• Contact with the cell delivers a ‘lethal hit’.
• It releases cytolytic molecules from its intracellular stores that trigger apoptosis in the target cell.
• The CTL (cytotoxic T lymphocyte) can then detach and target another cell.

Question 19

Describe the CTL cytolytic proteins.

Answer 19

1. PERFORIN: forms pores in target cell membranes, allowing the entry of granzymes
2. ,GRANZYMES (A, B and C): serine-esterase proteases that induce apoptosis.
3. This acts at a specific synapse between the CTL and the target, thus limiting any ‘collateral’ damage.
4. It involved cytoskeletal reorganisation and granule release.
5. Granzymes activate caspases, which lead to apoptosis (Granzyme B can trigger the mitochondrial apoptotic pathway).
6. FasL (on the CTL) ligates the Fas receptor (on target cells), which also leads to the activation of caspases, which ultimately leads to apoptosis.
7. The killing of infected cells by CTL eliminates the reservoirs of infection.