L5 - Lymphocyte activation: T cells

Question 1

What are the types of effector T cells?

Answer 1

Cytotoxic T cells (CD8+) – kill infected cells

Helper T cells (CD4+) – secrete cytokines

Question 2

What are naive/virgin T cells?

Answer 2

Haven’t seen any antigens yet

Question 3

What happens to naive/virgin T cells once they exit the thymus?

Answer 3

Recirculate via blood/lympathics through secondary lymphoid tissue (lymph nodes & spleen)

Contact with specific Ag & APC leads to clonal proliferation & differentiation

Question 4

What happens in the lymphoid tissue?

Answer 4

T cells recognise Ag/MHC antigen on APCs

Array of APC are found, some specialised, trap & present Ag (in lymph nodes & spleen)

T cell effectors then migrate to sites of infection

Question 5

How do naive/virgin T cells survive?

Answer 5

Naïve T cells must encounter Ag for survival

Question 6

How do T cells get to where they need to be?

Answer 6

Enter lymph node from blood via high endothelial venules (HEV)

T cell area rich in dendritic cells & macrophages (APCs)

APC present specific antigen & deliver other activation signals (eg. cytokines)

T cells can then proliferate & leave as activated T cells – they know where to go

Question 7

What happens to T cells that don’t become activated?

Answer 7

T cells that are not activated leave lymph node via cortical sinuses into the lymphatics

Re-enter circulation – recycled for another day

Question 8

What are cell adhesion molecules (CAM)?

Answer 8

Molecules expressed on surface of T cells, bind ligands expressed on other cells

Different molecular sets mediate different interactions
– Naïve T cell with HEV
– T cell with APC
– Effector T cell & target cell

Question 9

T cell contact with APC

Answer 9

1. T cells contact APCs using CAMs
2. TCR scans APC peptide/MHC complexes
   – No recognition = disengages
   – Recognition = signal from TCR complex (CD3)

Question 10

What happens in TCR recognises MHC complex on APC?

Answer 10

1) Signal from TCR complex (CD3)
2) Increases affinity of CAM interactions
3) T cell divides
4) Progeny differentiate to effector cells
5) T cell-mediated response

Question 11

TCR affinity for MHC is very low - what does this mean?

Answer 11

The chances of the T cell hanging around are really low due to the poor affinity

T cell has to rely on other molecules to hold it to the APC

Question 12

How is the TCR held to the MHC molecule?

Answer 12

CD4 is on the T cell & interacts with MHC II – acts as Sellotape holding the cells together while the TCR scans the molecule

If the TCR recognises the peptide, it sends a signal & LFA-1 & ICAM-1 change in structure

Changes the affinity of them for each other to anchor the 2 cells together for long enough for the T cell to become activated

Question 13

What is LFA-1?

Answer 13

Leukocyte function-associated antigen (integrin)

Question 14

What is ICAM-1?

Answer 14

Intracellular adhesion molecule

Question 15

Co-stimulation of T cells

Answer 15

Need 3 signals to become an effector cell - fail safe mechanism

Signal 1
Signal 2
Signal 3

Question 16

Co-stimulation of T cells

SIGNAL 1

Answer 16

Naïve T cells receive a signal from TCR containing MHC/peptide on APC

Involved CD3 & zeta

Question 17

Co-stimulation of T cells

SIGNAL 2

Answer 17

Professional APC also express co-stimulatory molecules (B7.1 & B7.2) that bind CD28 expressed by naïve T cells & delivers signal 2 to the T cell

B7.1 is also called CD80
B7.2 is also called CD86

Question 18

Co-stimulation of T cells

SIGNAL 3

Answer 18

APC also release cytokines which bind cytokine receptors now upregulated on naïve T cells which deliver signal 3

Question 19

What happens once the T cell is activated by all 3 signals?

Answer 19

Activated T cells express ICOS & CTLA-4

Question 20

What does ICOS do?

Answer 20

ICOS (related to CD28) binds ICOSL on APC to induce cytokine secretion by T cells

Question 21

What does CTLA-4 do?

Answer 21

CTLA-4 is highly related to CD28, & shows stronger binding to B7 than CD28

Binding of CTLA-4 to B7 on APC delivers a negative signal to activated T cell – acts as an antagonist to CD28 & serves to dampen down the T cell response

Question 22

Importance of CTLA-4

Answer 22

A protein receptor that functions as an immune checkpoint and down-regulates immune responses

Once T cells are triggered, there are other T cells that need shutting down – don’t want to keep triggering cells

Without it you get autoimmune diseases

Question 23

Cancer treatment & CTLA-4

Answer 23

Treatment of cancer patients with anti-CTLA-4 can enhance the immune response to the tumour but can also induce autoimmune reactions

Question 24

Activation of APC

Answer 24

APC express receptors for microbial molecules (PRR)
• Eg. carbohydrates, lipopolysaccharides (LPS)

Binding these pathogen-associated molecules activates APC – known as the danger signal
Leads to APC upregulation of MHC & co-stimulator molecules

Question 25

Why is the activation of APCs important in T cell activation?

Answer 25

Ensures signal 2 to activate T cell-mediated response only occurs during infection If a T cell receives signal 1 without signal 2, then it is functionally inactivated (anergic) & will not subsequently respond Ensures only pathogen-activated APC can activate T cells

Question 26

Co-stimulation: signal 3 (cytokines)

Answer 26

Dictate the differentiation of activated CD4 cells into different sub-sets of effector cells Tells T cells what kind of T cell it needs to become depending on the cytokines that T cell makes

Question 27

What are APCs?

Answer 27

Controllers of the immune response Express MHC class II molecules Dendritic cells – only function is to present Ag & crucial for activation of naïve T cells – Dedicated to activate CD4 cells – don’t do anything else Macrophages & B cells are also key APCs – present antigen in order to receive help from effector T cells

Question 28

What are the 2 types of dendritic cells?

Answer 28

Myeloid – conventional DC (DC2,3) • Potent APC • Involved in activation of naïve T cells Plasmacytoid DC (pDC, DC6) • Important in viral infection • Secrete several type I alpha & beta interferons • Express TLR7&9 – sense viral antigens

Question 29

Myeloid DC

Answer 29

* Key APC that initiate T cell responses * Bone marrow derived * Immature form found in epithelia (eg. skin) * Do not express co-stimulatory molecules (B7) until activated/matured * Induced to mature & migrate to lymph node following ‘danger signal’ activation/maturation (Looking for bad things to happen – as soon as they detect something they become activated & take a piece of the damage to the lymph nodes to the B & T cells)

Question 30

Activated myeloid DC

Answer 30

DC MHC I & II will be loaded with peptides from pathogens they encounters in peripheral tissues Their levels of co-stimulatory molecules (eg. B7.1/2) will be very high They will express high levels of adhesion molecules

Question 31

Cross-presentation of DC cells

Answer 31

``` Some specialised DC (DC1) process exogenous Ag & present it via MHC class I molecules – Normally class II – Done by cross-presentation ``` This allows DC to activate CD8 T cells which can then kill other infected but non-APC which are expressing viral antigens on class I Means both CD4 & CD8 can both be activated in the lymph node in response to DCs

Question 32

Macrophages as APC

Answer 32

Function as scavengers/killers of pathogens but also important APC for extracellular pathogens (eg. bacteria & fungi) Highly phagocytic – express many receptors for pathogen uptake (eg. carbohydrate & complement receptors) Once activated by T cells secrete many inflammatory cytokines

Question 33

B cells as APC

Answer 33

* Very poor at phagocytosis * Internalise soluble Ag for processing & presentation by BCR * Ag binding to BCR up-regulates B7 – B cells are capable of providing signal 2 to activate T cells * Similar to DC – found in lymph nodes presenting to T cells * Can recognise antigens in lots of different ways * B cells act as Ag-specific APC

Question 34

IL-2

Answer 34

A key cytokine for T cell survival • Once T cell becomes activated they express a high affinity IL-2R • IL-2 binding to IL-2R on activated T cells leads to T cell proliferation Target of immunosuppressive drugs – eg. cyclosporin

Question 35

When do T cells differentiate into effector T cells?

Answer 35

Following activation by APC Type of effector sub-set generated is dictated by signal 3 (cytokines) from APC & the pathogen

Question 36

Effector T cells

Answer 36

Display effector function when TCR engaged – No longer require co-stimulation – Change expression of adhesion molecules No longer enter lymph nodes But enter tissues via activated endothelia – at sites of infection & inflammation Go where they are needed

Question 37

Activation of CD8+ T cells

Answer 37

Require high levels of co-stimulator activity Some CD8+ responses can be activated directly by APC Or may require additional help from CD4+ T cells